Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DDP-IV)

ABSTRACT

The present invention relates to compounds which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis, and various immunomodulatory diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 12/727,558,filed on Mar. 19, 2010, now U.S. Pat. No. 8,119,664, which is adivisional of U.S. patent application Ser. No. 11/828,099, filed Jul.25, 2007, which is a divisional of U.S. patent application Ser. No.10/788,993, filed Feb. 27, 2004, now U.S. Pat. No. 7,262,207, which is acontinuation-in-part of U.S. patent application Ser. No. 10/659,860,filed Sep. 11, 2003, which claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/412,084, filed on Sep. 19, 2002, the contents ofall of which are fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds which inhibit dipeptidylpeptidase IV (DPP-IV) and are useful for the prevention or treatment ofdiabetes, especially type II diabetes, as well as hyperglycemia,Syndrome X, hyperinsulinemia, obesity, atherosclerosis, and variousimmunomodulatory diseases.

BACKGROUND OF THE INVENTION

Dipeptidyl peptidase IV (DPP-IV, CD26, EC 3.4.14.5) is a serine proteasewith specificity for cleaving Xaa-Pro and, to a lesser extent, Xaa-Aladipeptides from the N-termini of polypeptides and proteins. DPP-IV is anon-classical serine protease in that the catalytic triad ofSer-Asp-His, found in the C-terminal region of the enzyme, is in reverseorder to that found in classical serine proteases. DPP-IV is widelyexpressed in mammalian tissue as a type II integral membrane protein.DPP-IV is expressed on the surface of differentiated epithelial cells ofthe intestine, liver, kidney proximal tubules, prostate, corpus luteum,and on leukocyte subsets such as lymphocytes and macrophages. A solubleform of the enzyme is found in scrum that has structure and functionidentical to the membrane-bound form of the enzyme but lacks thehydrophobic transmembrane domain.

DPP-IV has many physiologically relevant substrates including chemokinessuch as, RANTES (regulated on activation normal T cell expressed andsecreted), eotaxin, and macrophage-derived chemokine, neuropeptides suchas NPY (neuropeptide Y) and substance P, vasoactive peptides, andincretins such as GLP-1 (glucagon-like peptide-1) and GIP (gastricinhibitory peptide/glucose-dependent insulinotropic polypeptide). GLP-1is a 30 amino acid peptide hormone produced in the L cells of the distalsmall intestine in response to ingested nutrients. GLP-1 binding to itsreceptor on various tissues stimulates insulin gene expression,biosynthesis and glucose-dependent insulin secretion, inhibits glucagonsecretion, promotes satiety, slows gastric emptying and promotes growthof pancreatic beta cells. Based on this profile, GLP-1-based therapiesare expected to be beneficial in the treatment of type II diabetes andobesity. Studies in which type II diabetic patients have been infusedwith GLP-1 have demonstrated efficacy in normalizing both fasted andprandial glycemia. However, active GLP-1 (7-36) amide is rapidlyconverted by DPP-IV to GLP-1 (9-36), which is inactive or is a receptorantagonist. The short half-life of GLP-1 in the circulation (1-1.5minutes) is a major obstacle to its use as a therapeutic agent. Tocircumvent the drawback of the short half-life of GLP-1, inhibitors ofDPP-IV, the primary degradative enzyme of GLP-1, increase the level ofactive circulating GLP-1 (7-36) amide. DPP-IV inhibitors have beendemonstrated to improve glucose tolerance in type II diabetes.

Therefore, the inhibition of DPP-IV can provide therapeutic treatmentfor type II diabetes.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I),

or pharmaceutically acceptable salts or prodrugs thereof, wherein

X is a member selected from the group consisting of CH₂, CHF and CF₂;

R is a member selected from the group consisting of alkylcarbonyl,arylcarbonyl, cyano, heterocyclecarbonyl, R₄R₅NC(O)—, B(OR₆)₂,(1,2,3)-dioxoborolane and 4,4,5,5-tetramethyl-(1,2,3)-dioxoborolane;

R₁ is a member selected from the group consisting of alkoxyalkyl, alkyl,alkylcarbonyl, alkenyl, alkynyl, allenyl, arylalkyl, cycloalkyl,cycloalkylalkyl, cyano, haloalkyl, haloalkenyl, heterocyclealkyl, andhydroxyalkyl;

R₂ and R₃ are independently selected from the group consisting ofhydrogen, alkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, andhydroxyalkyl; or R₂ and R₃ taken together with the atoms to which theyare attached form a mono or bicyclic heterocycle selected from the groupconsisting of 2-indolinyl, 2-indolyl, 3-isoquinoline, 2-piperazine,2-piperidine, 2-pyrrolidine, 2-pyrrole, 2-pyridine, 2-quinolinyl,2-tetrahydroquinolinyl, and 3-tetrahydroisoquinolinyl, wherein saidheterocycle may be substituted with 0, 1, 2 or 3 substituentsindependently selected from alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy, carboxy,carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkyl, hydroxy,hydroxyalkyl, mercapto, nitro, phenyl, R_(A)R_(B)N—, R_(C)R_(D)NC(O)—,and R_(C)R_(D)NS(O)₂—;

R₄, R₅ and R₆ are each independently selected from the group consistingof hydrogen, alkyl, and arylalkyl;

R_(A) and R_(B) are each independently selected from the groupconsisting of alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl; orR_(A) and R_(B) taken together with the nitrogen to which they areattached form a ring selected from the group consisting of piperidine,piperazine and morpholine; and

R_(C) and R_(D) are each independently selected from the groupconsisting of hydrogen and alkyl.

According to an embodiment of the present invention, there is provided amethod to improve glucose tolerance in type II diabetes comprisingadministering a therapeutically effective amount of a compound offormula (I). According to another embodiment of the present invention,there is provided a method for treating type 2 diabetes, insulinresistance, hyperinsulinemia, impaired glucose tolerance, obesity,hypercholesterolemia, and hypertriglyceridemia comprising administeringa therapeutically effective amount of a compound of formula (I).

According to still another embodiment, the present invention is directedto pharmaceutical compositions comprising a therapeutically effectiveamount of a compound of formula (I) in combination with apharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl,” as used herein, refers to a straight or branchedchain hydrocarbon containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy,” as used herein, refers to an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl,” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of alkoxyalkylinclude, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl,2-methoxyethyl, and methoxymethyl.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkyl,” as used herein, refers to a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl. The alkyl groups of the present invention may be optionallysubstituted with 0, 1 or 2 substituents that are members selected fromthe group consisting of alkoxy, alkoxycarbonyl, alkylcarbonyl,alkylcarbonyloxy, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl,cyano, cyanoalkyl, formyl, halogen, hydroxy, alkoxycarbonylNR_(g),alkylNR_(g) wherein R_(g) is a member selected from the group consistingof hydrogen and alkyl.

The term “alkylcarbonyl,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylsulfonyl,” as used herein, refers to an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkynyl,” as used herein, refers to a straight or branchedchain hydrocarbon group containing from 2 to 10 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of alkynyl include, but are not limited, to acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The alkynyl groups of this invention can be substituted with 0, 1, 2, or3 substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl, alkylcarbonylalkyl,heterocycle, heterocyclealkyl, hydroxy, and hydroxyalkyl.

The term “allenyl,” as used herein, refers to a straight or branchedchain hydrocarbon containing from 3 to 10 carbons and containing twodouble bonds between three contiguous carbons formed by the removal offour hydrogens. Representative examples of alkenyl include, but are notlimited to, propa-1,2 dienyl, penta-1,2 dienyl, penta-2,3 dienyl,hexa-1,2-dienyl and the like.

The term “aryl,” as used herein, refers to a monocyclic-ring system, ora bicyclic- or a tricyclic-fused ring system wherein one or more of thefused rings are aromatic. Representative examples of aryl include, butare not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl,naphthyl, phenyl, and tetrahydronaphthyl.

The aryl groups of the present invention can be substituted with 0, 1,2, or 3 substituents independently selected from alkyl, alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkyl,heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, mercapto, nitro,phenyl, R_(E)R_(F)N—, R_(G)R_(H)NC(O)—, and R_(G)R_(H)NS(O)₂—, whereinR_(E) and R_(F) are each independently selected from the groupconsisting of alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, andR_(G) and R_(II) are each independently selected from the groupconsisting of hydrogen and alkyl.

The term “arylalkoxy,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of arylalkoxyinclude, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy,and 5-phenylpentyloxy.

The term “arylalkyl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “arylcarbonyl,” as used herein, refers to an aryl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofarylcarbonyl include, but are not limited to, benzoyl and naphthoyl.

The term “carbonyl,” as used herein, refers to a —C(O)— group.

The term “carboxy,” as used herein, refers to a —CO₂H group.

The term “cyano,” as used herein, refers to a —CN group.

The term “cyanoalkyl,” as used herein, refers to a cyano group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cyanoalkyl include,but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkyl,” as used herein, refers to a monocyclic, bicyclic,or tricyclic ring system. Monocyclic ring systems are exemplified by asaturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms.Examples of monocyclic ring systems include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ringsystems are exemplified by a bridged monocyclic ring system in which twonon-adjacent carbon atoms of the monocyclic ring are linked by analkylene bridge of between one and three additional carbon atoms.Representative examples of bicyclic ring systems include, but are notlimited to, bicyclo(3.1.1)heptane, bicyclo(2.2.1)heptane,bicyclo(2.2.2)octane, bicyclo(3.2.2)nonane, bicyclo(3.3.1)nonane, andbicyclo(4.2.1)nonane. Tricyclic ring systems are exemplified by abicyclic ring system in which two non-adjacent carbon atoms of thebicyclic ring are linked by a bond or an alkylene bridge of between oneand three carbon atoms. Representative examples of tricyclic-ringsystems include, but are not limited to, tricyclo(3.3.1.0^(3,7))nonaneand tricyclo(3.3.1.1^(3,7))decane (adamantane).

The cycloalkyl groups of this invention may be substituted with 0, 1, 2or 3 substituents selected from alkyl, alkylcarbonyl, alkoxy,alkoxycarbonyl, alkenyl, alkynyl, aryl, cyano, halogen, hydroxy,hydroxyalkyl, nitro, R_(E)R_(F)N—, R_(G)R_(H)NC(O)—, andR_(G)R_(H)NS(O)₂—, wherein R_(E) and R_(F) are each independentlyselected from the group consisting of alkyl, alkylcarbonyl,alkoxycarbonyl, alkylsulfonyl, and R_(G) and R_(H) are eachindependently selected from the group consisting of hydrogen, arylalkyl,heterocyclealkyl, heterocycle and alkyl.

The term “cycloalkylalkyl,” as used herein, refers to a cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofcycloalkylalkyl include, but are not limited to, cyclopropylmethyl,2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and4-cycloheptylbutyl.

The term “halo” or “halogen,” as used herein, refers to —Cl, —Br, —I or—F.

The term “haloalkyl,” as used herein, refers to at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “haloalkenyl,” as used herein, refers to at least one halogen,as defined herein, appended to the parent molecular moiety through analkenyl group, as defined herein. Representative examples of haloalkenylinclude, but are not limited to, chloroethylenyl, 2-fluoroethylene,trifluorobutenyl, and dichloropropenyl.

The term “heterocycle” or “heterocyclic,” as used herein, refers to amonocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systemsare exemplified by any 3- or 4-membered ring containing a heteroatomindependently selected from oxygen, nitrogen and sulfur; or a 5-, 6- or7-membered ring containing one, two or three heteroatoms wherein theheteroatoms are independently selected from nitrogen, oxygen and sulfur.The 5-membered ring has from 0-2 double bonds and the 6- and 7-memberedring have from 0-3 double bonds. Representative examples of monocyclicring systems include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl,imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl,isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl,oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl,thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl,thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone),thiopyranyl, triazinyl, triazolyl, and trithianyl. Bicyclic ring systemsare exemplified by any of the above monocyclic ring systems fused to anaryl group as defined herein, a cycloalkyl group as defined herein, oranother monocyclic ring system. Representative examples of bicyclic ringsystems include but are not limited to, for example, benzimidazolyl,benzodioxinyl, benzothiazolyl, benzothienyl, benzotriazolyl,benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, cinnolinyl,indazolyl, indolyl, 2,3-dihydroindolyl, indolizinyl, naphthyridinyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,phthalazinyl, 4H-pyrido(1,2-a)pyrimidin-4-one, pyranopyridinyl,quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, and thiopyranopyridinyl.Tricyclic rings systems are exemplified by any of the above bicyclicring systems fused to an aryl group as defined herein, a cycloalkylgroup as defined herein, or a monocyclic ring system. Representativeexamples of tricyclic ring systems include, but are not limited to,acridinyl, carbazolyl, carbolinyl, dibenzo(b,d)furanyl,dibenzo(b,d)thienyl, naphtho(2,3-b)furan, naphtho(2,3-b)thienyl,phenazinyl, phenothiazinyl, phenoxazinyl, thianthrenyl, thioxanthenyland xanthenyl.

According to the present invention, heterocycles can be substituted with0, 1, 2 or 3 substituents independently selected from alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy, carboxy,carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkyl, hydroxy,hydroxyalkyl, mercapto, nitro, phenyl, sulfonyl, R_(E)R_(F)N—,R_(G)R_(H)NC(O)—, and R_(G)R_(H)NS(O)₂—, wherein R_(E) and R_(F) areeach independently selected from the group consisting of alkyl,alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, and R_(G) and R_(H) areeach independently selected from the group consisting of hydrogen andalkyl.

The term “heterocyclealkyl,” as used herein, refers to a heterocycle, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heterocyclealkylinclude, but are not limited to, pyridin-3-ylmethyl and2-pyrimidin-2-ylpropyl and the like.

The term “hydroxy,” as used herein, refers to an —OH group.

The term “hydroxyalkyl,” as used herein, refers to a hydroxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of hydroxyalkylinclude, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl,3-hydroxybutyl and the like.

The term “heterocyclecarbonyl,” as used herein, refers to a heterocycle,as defined herein, appended to the parent molecular moiety through ancarbonyl group, as defined herein. Representative examples ofheterocyclecarbonyl include, but are not limited to,pyridin-3-ylcarbonyl and 2-pyrimidin-2-ylcarbonyl and the like.

The term “nitro,” as used herein, refers to a —NO₂ group.

The present invention is directed to compounds of formula (I), whereinR, R₁, R₂, R₃, R₄, R₅, R₆, R_(A), R_(B), R_(C) and R_(D) are definedherein.

The present invention is also directed to a method of treating disordersmediated by DPP-IV through inhibition of enzymatic activity. Disordersknown to be regulated through enzymatic activity are diabetes,especially type II diabetes, as well as hyperglycemia, Syndrome X,hyperinsulinemia, obesity, atherosclerosis, various immunomodulatorydiseases. Therefore, according to an embodiment of the present inventionthere are provided compounds of formula (I), which are useful for thetreatment of diabetes, especially type II diabetes, as well ashyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis,and various immunomodulatory diseases.

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano and wherein X,R₁, R₂ R₃, R₄, R₅ and R₆ are as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, alkynyl, andcycloalkyl and wherein X, R₂, and R₃ are as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ isa member selected from the group consisting of alkoxyalkyl, alkyl,cycloalkyl, cycloalkylalkyl, arylalkyl, and heterocyclealkyl and whereinX, and R₃ are as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ isselected from the group consisting of alkyl, cycloalkyl, andheterocycle; R₃ is hydrogen and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkynyl, wherein alkynyl isethynyl and propynyl; R₂ is a member selected from the group consistingof alkyl, cycloalkyl, and heterocycle; R₃ is hydrogen and wherein X isas defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ isa member selected from the group consisting of alkyl, cycloalkyl, andheterocycle; R₃ is cycloalkyl, wherein cycloalkyl is a member selectedfrom the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cycloheptyl, and cyclooctyl and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is alkynyl,wherein alkynyl is ethynyl or propynyl; R₂ is hydrogen; R₃ iscycloalkyl, wherein cycloalkyl is a member selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, andcyclooctyl and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ ishydrogen; and R₃ is cycloalkyl, wherein cycloalkyl is a member selectedfrom the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cycloheptyl, and cyclooctyl and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ isa member selected from the group consisting of alkyl, cycloalkyl, andheterocycle; and R₃ is R₉—O-cyclohexyl; R₉ is a member selected from thegroup consisting of hydrogen, aryl, and heterocycle and wherein X is asdefined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is alkynyl,wherein alkynyl is ethynyl or propynyl; R₂ is hydrogen; and R₃ is

R₉ is a member selected from the group consisting of hydrogen, aryl, andheterocycle and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ ishydrogen; R₃ is

R₉ is a member selected from the group consisting of hydrogen, aryl, andheterocycle and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ isa member selected from the group consisting of alkyl, cycloalkyl, andheterocycle; R₃ is alkyl; wherein the alkyl group of R₃ is substitutedwith a member of the group consisting of alkoxy, alkoxycarbonyl,alkoxycarbonylNH, alkylNH, carboxy, and hydroxy and wherein X is asdefined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is alkynyl,wherein alkynyl is ethynyl or propynyl; R₂ is hydrogen; R₃ is alkyl;wherein the alkyl group of R₃ is substituted with a member of the groupconsisting of alkoxy, alkoxycarbonyl, alkoxycarbonylNH, alkylNH,carboxy, and hydroxy; and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ ishydrogen; R₃ is alkyl; wherein the alkyl group of R₃ is substituted witha member of the group consisting of alkoxy, alkoxycarbonyl,alkoxycarbonylNH, alkylNH, carboxy, and hydroxy; and wherein X is asdefined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ isselected from the group consisting of alkyl, cycloalkyl, andheterocycle; R₃ is a member selected from the group consisting of aryland heterocycle; wherein said heterocycle is a member selected from thegroup consisting of azetidinyl, azepanyl, aziridinyl, diazepinyl,1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl,imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl,isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl,oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl,piperazinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl,thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl,thiazolidinyl, thienyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl,triazinyl, triazolyl, and trithianyl and wherein X is as defined informula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is alkynyl,wherein alkynyl is ethynyl or propynyl, R₂ is hydrogen; and R₃ is amember selected from the group consisting of aryl and heterocycle;wherein said heterocycle is a member selected from the group consistingof azetidinyl, azepanyl, aziridinyl, diazepinyl, 1,3-dioxolanyl,dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl,isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl,oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl,pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl,thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl,thiazolidinyl, thienyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl,triazinyl, triazolyl, and trithianyl; and wherein X is as defined informula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ ishydrogen; R₃ is a member selected from the group consisting of aryl andheterocycle; wherein said heterocycle is a member selected from thegroup consisting of azetidinyl, azepanyl, aziridinyl, diazepinyl,1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl,imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl,isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl,oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl,piperazinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl,thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl,thiazolidinyl, thienyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl,triazinyl, triazolyl, and trithianyl; and wherein X is as defined informula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl and alkynyl; R₂ is hydrogen;R₃ is heterocycle; wherein said heterocycle is piperidine, and wherein Xis as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is alkyl,alkenyl, and alkynyl; R₂ is a member selected from the group consistingof alkyl, cycloalkyl, and heterocycle; R₃ is a member selected from thegroup consisting of arylalkyl and heterocyclealkyl; and wherein X is asdefined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is alkynyl,wherein alkynyl is ethynyl or propynyl; R₂ is hydrogen; R₃ is a memberselected from the group consisting of arylalkyl and heterocyclealkyl;and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl and alkynyl; R₂ is a memberselected from the group consisting of alkyl, cycloalkyl, andheterocycle; R₃ is

R₇ is a member selected from the group consisting of hydrogen and alkyl;R₈ is a member selected from the group consisting of hydrogen,alkylcarbonyl, aryl and heterocycle; and wherein X is as defined informula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano, R₁ is alkynyl,wherein alkynyl is ethynyl or propynyl, R₂ is hydrogen; R₃ is

R₇ is a member selected from the group consisting of hydrogen and alkyl;R₈ is a member selected from the group consisting of hydrogen,alkylcarbonyl, aryl and heterocycle; and wherein X is as defined informula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano, R₁ is a memberselected from the group consisting of alkyl and alkynyl; R₂ is hydrogen;R₃ is

R₇ is a member selected from the group consisting of hydrogen and alkyl;R₈ is a member selected from the group consisting of arylcarbonyl, andheterocyclecarbonyl-; and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is alkynyl,wherein alkynyl is ethynyl or propynyl; R₂ is hydrogen; R₃ is

R₇ is a member selected from the group consisting of hydrogen and alkyl;R₈ is a member selected from the group consisting of arylcarbonyl andheterocyclecarbonyl-; and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ ishydrogen; R₃ is heterocycle, wherein said heterocycle is

R₇ is a member selected from the group consisting of hydrogen and alkyl;R₈ is a member selected from the group consisting of aryl, heterocycle;and wherein X is as defined in formula (I). Aryl and heterocycles at theR₈ position may be substituted with 0, 1, 2 or 3 substituentsindependently selected from the group consisting of alkyl, alkoxy,alkoxyalkyl, alkoxy alkenyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl,alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxycarbonylalkenyl, alkylsulfonyl, alkylsulfonylalkyl,alkylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl,aminosulfonylalkyl, aminosulfonylalkenyl, carboxaldehyde,(carboxaldehyde)alkyl, (carboxaldehyde)alkenyl, carboxamido,carboxamidoalkyl, carboxamidoalkenyl, carboxy, carboxyalkyl,carboxyalkenyl, cyano, cyanoalkyl, cyanoalkenyl, halo, haloalkyl,haloalkenyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, nitro,perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl,perfluoroalkoxyalkenyl thioalkoxy, thioalkoxyalkyl, thioalkoxyalkenyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, and unsubstituted or substituted heterocycle.

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl and alkynyl; R₂ is hydrogen;R₃ is heterocycle, wherein said heterocycle is

R₇ is a member selected from the group consisting of hydrogen and alkyl;R₈ is a member selected from the group consisting of arylcarbonyl andheterocyclecarbonyl; and wherein X is as defined in formula (I). Thearyl group of the arylcarbonyl group of R₈ of the compounds of thepresent invention may optionally substituted with 0, 1, 2 or 3substituents independently selected from alkyl, alkoxy, alkoxyalkyl,alkoxyalkenyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl,alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxycarbonylalkenyl, alkylsulfonyl, alkylsulfonylalkyl,alkylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl,aminosulfonylalkyl, aminosulfonylalkenyl, carboxaldehyde,(carboxaldehyde)alkyl, (carboxaldehyde)alkenyl, carboxamido,carboxamidoalkyl, carboxamidoalkenyl, carboxy, carboxyalkyl,carboxyalkenyl, cyano, cyanoalkyl, cyanoalkenyl, halo, haloalkyl,haloalkenyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, nitro,perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl,perfluoroalkoxyalkenyl thioalkoxy, thioalkoxyalkyl, thioalkoxyalkenyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, and unsubstituted or substituted heterocycle. Theheterocycle group of heterocyclecarbonyl may be optionally substitutedas described above for the aryl group of the arylcarbonyl group.

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl and alkynyl; R₂ is a memberselected from the group consisting of alkyl, cycloalkyl, andheterocycle; R₃ is a member selected from the group consisting ofaryl-O-alkyl, aryl-NH-alkyl, heterocycle-O-alkyl andheterocycle-NH-alkyl; and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano, R₁ is alkynyl,wherein alkynyl is ethynyl or propynyl, R₂ is hydrogen; R₃ is a memberselected from the group consisting of aryl-O-alkyl, aryl-NH-alkyl,heterocycle-O-alkyl and heterocycle-NH-alkyl; and wherein X is asdefined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl and alkynyl; R₂ and R₃ takentogether with the atoms they are attached form a mono or bicyclicheterocycle selected from the group consisting of 3-isoquinoline,2-pyrrolidinyl, 2-quinolinyl, 2-tetrahydroquinolinyl, and3-tetrahydroisoquinolinyl; and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is alkynyl,wherein alkynyl is ethynyl or propynyl; R₂ and R₃ taken together withthe atoms they are attached form a mono or bicyclic heterocycle selectedfrom the group consisting of 3-isoquinoline, 2-pyrrolidinyl,2-quinolinyl, 2-tetrahydroquinolinyl, and 3-tetrahydroisoquinolinyl; andwherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, alkynyl; R₂ and R₃taken together with the atoms they are attached form 3-isoquinolinyl,and wherein X is as defined in formula (I).

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl and alkynyl; R₂ is hydrogen;R₃ is R₉—O-cycloalkyl, wherein said R₉—O-cycloalkyl is

R₇ is a member selected from the group consisting of hydrogen and alkyl;R₉ is a member selected from the group consisting of hydrogen, aryl,pyridine, and pyrimidine; and wherein X is as defined in formula (I).The aryl group or pyridyl group of R₉ may be optionally substituted with0, 1, 2 or 3 substituents independently selected from alkyl, alkoxy,alkoxyalkyl, alkoxyalkenyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl,alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxycarbonylalkenyl, alkylsulfonyl, alkylsulfonylalkyl,alkylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl,aminosulfonylalkyl, aminosulfonylalkenyl, carboxaldehyde,(carboxaldehyde)alkyl, (carboxaldehyde)alkenyl, carboxamido,carboxamidoalkyl, carboxamidoalkenyl, carboxy, carboxyalkyl,carboxyalkenyl, cyano, cyanoalkyl, cyanoalkenyl, halo, haloalkyl,haloalkenyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, nitro,perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl,perfluoroalkoxyalkenyl thioalkoxy, thioalkoxyalkyl, thioalkoxyalkenyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, and unsubstituted or substituted heterocycle.

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, alkynyl; R₂ ishydrogen; R₃ is a member selected from the group consisting of arylalkyland heterocyclealkyl; and wherein X is as defined in formula (I). Thearyl group of arylalkyl of and the heterocycle of heterocyclealkyl of R₃is optionally substituted with 0, 1, 2 or 3 substituents independentlyselected from alkyl, alkoxy, alkoxyalkyl, alkoxyalkenyl, alkanoyl,alkanoyloxy, alkanoyloxyalkyl, alkanoyloxyalkenyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkylsulfonyl,alkylsulfonylalkyl, alkylsulfonylalkenyl, amino, aminoalkyl,aminoalkenyl, aminosulfonyl, aminosulfonylalkyl, aminosulfonylalkenyl,carboxaldehyde, (carboxaldehyde)alkyl, (carboxaldehyde)alkenyl,carboxamido, carboxamidoalkyl, carboxamidoalkenyl, carboxy,carboxyalkyl, carboxyalkenyl, cyano, cyanoalkyl, cyanoalkenyl, halo,haloalkyl, haloalkenyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, nitro,perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl,perfluoroalkoxyalkenyl thioalkoxy, thioalkoxyalkyl, thioalkoxyalkenyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, and unsubstituted or substituted heterocycle. In oneparticular embodiment of the present invention the heterocycle ofheterocyclealkyl is pyridine.

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl and alkynyl; R₂ is hydrogen;R₃ is a member selected from the group consisting of arylNHalkyl-,aryl-O-alkyl-, heterocycleNHalkyl- and heterocycle-O-alkyl-; and whereinX is as defined in formula (I). The aryl group of arylNHalkyl- andaryl-O-alkyl- and the heterocycle of heterocycleNHalkyl- andheterocycle-O-alkyl- of R₃ is optionally substituted with 0, 1, 2 orsubstituents independently selected from alkyl, alkoxy, alkoxyalkyl,alkoxyalkenyl, alkanoyl, alkanoyloxy, alkanoyloxyalkyl,alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxycarbonylalkenyl, alkylsulfonyl, alkylsulfonylalkyl,alkylsulfonylalkenyl, amino, aminoalkyl, aminoalkenyl, aminosulfonyl,aminosulfonylalkyl, aminosulfonylalkenyl, carboxaldehyde,(carboxaldehyde)alkyl, (carboxaldehyde)alkenyl, carboxamido,carboxamidoalkyl, carboxamidoalkenyl, carboxy, carboxyalkyl,carboxyalkenyl, cyano, cyanoalkyl, cyanoalkenyl, halo, haloalkyl,haloalkenyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, nitro,perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkyl,perfluoroalkoxyalkenyl thioalkoxy, thio alkoxyalkyl, thioalkoxyalkenyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, and unsubstituted or substituted heterocycle.

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl and alkynyl; R₂ is hydrogen;R₃ is alkyl; and wherein X is as defined in formula (I). In oneparticular embodiment of the present invention, the alkyl group of R₃ issubstituted with 0, 1, 2 or 3 substituents independently selected fromalkoxy, alkoxyalkyl, alkoxyalkenyl, alkanoyl, alkanoyloxy,alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkenyl,alkylsulfonyl, alkylsulfonylalkenyl, amino, aminoalkenyl, aminosulfonyl,aminosulfonylalkenyl, carboxaldehyde, (carboxaldehyde)alkenyl,carboxamido, carboxamidoalkenyl, carboxy, carboxyalkenyl, cyano,cyanoalkenyl, halo, haloalkenyl, hydroxy, hydroxyalkenyl, nitro,perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkenyl thioalkoxy,thioalkoxyalkenyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, and unsubstituted or substituted heterocycle.

According to a further embodiment of the present invention there isprovided a compound of formula (I), wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ ishydrogen; R₃ is a member selected from the group consisting ofbicycloalkyl, cycloalkyl, heterocycle and tricycloalkyl; and wherein Xis as defined in formula (I). The bicycloalkyl, cycloalkyl, heterocycleor tricycloalkyl of R₃ of the present invention may be optionallysubstituted with 0, 1, 2 or 3 substituents independently selected fromalkoxy, alkoxyalkyl, alkoxyalkenyl, alkanoyl, alkanoyloxy,alkanoyloxyalkenyl, alkoxycarbonyl, alkoxycarbonylalkenyl,alkylsulfonyl, alkylsulfonylalkenyl, amino, aminoalkenyl, aminosulfonyl,aminosulfonylalkenyl, carboxaldehyde, (carboxaldehyde)alkenyl,carboxamido, carboxamidoalkenyl, carboxy, carboxyalkenyl, cyano,cyanoalkenyl, halo, haloalkenyl, hydroxy, hydroxyalkenyl, nitro,perfluoroalkyl, perfluoroalkoxy, perfluoroalkoxyalkenyl thioalkoxy,thioalkoxyalkenyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, and unsubstituted or substituted heterocycle.

Specific compounds of the present invention include, but are not limitedto:

-   (2S,5R)-5-ethynyl-1-L-leucylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-((3S)-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-vinylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5S)-5-ethyl-1-L-leucylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-ethylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-((1R,2R,4S)-bicyclo(2.2.1)hept-2-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-methyl-1-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(3-cyano-pyridin-2-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(1-(3-cyano-pyridin-3-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-methoxycarbonylbenzoyl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1-(4-chlorobenzoyl)piperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1-(5-chloropyridin-2-yl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(1-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(1-isonicotinoyl-4-methylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(5-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(5-cyano-pyridin-3-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-trans(4-hydroxycyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-trans{(4′-fluoro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-trans(4-(trifluoromethoxy)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-hydroxy-1-methylcyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(pyridin-3-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-trans((5-chloropyridin-3-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(4-cyanophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-trans{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-trans(3-pyridin-4-yl-4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(4-trans(pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(5-cyano-pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(4-trans(pyrimidin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(4-trans(5-cyano-pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4    trans-(4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-((5-fluoropyridin-3-yl)oxy)-1-methylcyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-trans(4-carboxy-phenoxy)cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-(2-(2-oxopyrrolidin-1-yl)-4-trans    (trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-(4-cyano-2-methoxyphenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-trans((5-fluoropyridin-3-yl)oxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-trans((5-bromopyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(4-trans(pyridin-3-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(1,1,3,3-tetramethylbutyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1,1-dimethyl-2-(5-cyano-pyridin-2-yloxy)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-(tert-butyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1,1-dimethyl-2-(quinolin-4-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(2-(4-fluorophenyl)-1,1-dimethylethyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-(1,1-dimethylpropyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(2-(1,3-benzothiazol-2-ylamino)-1,1-dimethylethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-((1R,4S)-bicyclo(2.2.1)hept-2-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-((3S)-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-1-adamantylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-cyclohexylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(1-(methoxymethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-tetrahydro-2H-pyran-4-ylglycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-((2S)-2-hydroxycyclopentyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-cyclopentylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(1-(hydroxymethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-L-leucylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-((2R)-2-amino-2-cyclohexylethanoyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-methylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-prop-1-ynyl-1-(N-{4-(4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1-(hydroxymethyl)cyclopentyl)glycyl}-5-prop-1-ynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-cyclopentylglycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-(N-cyclopentylglycyl)-5-methylpyrrolidine-2-carbonitrile;-   (2S,5S)-4,4-difluoro-5-methyl-1-L-valylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-{N-(1-(hydroxymethyl)cyclopentyl)glycyl}-5-methylpyrrolidine-2-carbonitrile;-   (2S,5S)-4,4-difluoro-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-vinylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-((2R)-2-amino-2-cyclopentylethanoyl)-5-vinylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-{N-((2R,5S)-hexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl}-5-methylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(1-tert-butoxycarbonyl-piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(1-5-cyano-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1-(4-chlorobenzoyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1-(3-cyanophenyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1-(4-cyanobenzoyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   N-(1-(3-chlorophenyl)-1H-indol-5-yl)-5-methyl-3-phenylisoxazole-4-carboxamide;-   (2S,5R)-1-{N-(1-(4-bromobenzoyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(4-cyano-2-fluorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(4-trans(3-fluorophenoxy)-1-methylcyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(3-cyanophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(1-methyl-4-{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-trans{(4′-fluoro-2-(trifluoromethyl)-1,1′-biphenyl-4-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-trans{(4′-fluoro-6-(trifluoromethyl)-1,1′-biphenyl-3-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-(3-cyano-4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(3-bromophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(4-cyano-3-fluorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-(2-cyano-4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(3-cyanophenoxy)-1-methylcyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(4-chlorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-trans{(6-methyl-4-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-trans(2-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-trans(4-pyridin-4-yl-3-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-(3-cyano-5-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(4-(4-fluorophenoxy)-1-methylcyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(4-(3-fluorophenoxy)-1-methylcyclohexyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(1-methyl-4-{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-trans(3-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-trans((3-bromopyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-trans{(4-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)-1-methylcyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(3-cyanophenoxy)-1-methylcyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-{4-(2-carboxy-4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(3-chlorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(1-methyl-4-trans{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(4-trans(4-bromophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{1,1-dimethyl-2-((3-cyano-6-methylpyridin-2-yl)amino)ethyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-(1,1-dimethyl-2-{(5-(trifluoromethyl)pyridin-2-yl)oxy}ethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-{1,1-dimethyl-2-((3-cyano-6-methylpyridin-2-yl)oxy)ethyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(tetrahydrofuran-2-ylmethyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(pyridin-2-ylmethyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(2-pyridin-4-ylethyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-((1-tert-butoxycarbonylpiperidin-4-yl)methyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(3-(methylamino)propyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-(4-tert-butoxycarbonylbutyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(3-hydroxy-2,2-dimethylpropyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1,1-dimethyl-2-(3-cyanopyridin-2-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-(1,1-dimethyl-2-{(4-(trifluoromethyl)pyrimidin-2-yl)amino}ethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1,1-dimethyl-2-(5-methoxycarbonylpyridine-2-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(2-(2-cyano-5-fluorophenoxy)-1,1-dimethylethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-iodobenzyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(3-(N-tert-butoxycarbonyl-N-methylamino)propyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(4-carboxybutyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-(2-{(3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino}ethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-(3-isopropoxypropyl)glycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-(1,1-dimethyl-2-(5-cyano-pyridin-2-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-(2-(4-carboxy-anilino)-1,1-dimethylethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-(1-(1-hydroxy-1-methylethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-((2R,5S)-hexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-cyclopentylglycyl-(N-methyl    1-aminocyclopentanecarboxy)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-cyclopropylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-piperidin-4-ylglycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-{N-((5R,7S)-3-hydroxy-1-adamantyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(N-tetrahydrofuran-3-ylglycyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-cycloheptylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-cyclobutylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(3-methyl-L-valyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-(3-pyridin-4-yl-L-alanyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-1-L-leucyl-5-prop-1-ynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(3-methyl-L-valyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-cyclobutylglycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-(N-(4-trans    hydroxycyclohexyl)glycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;-   (2S,5R)-1-{N-((2S)-2-hydroxycyclopentyl)glycyl}-5-prop-1-ynylpyrrolidine-2-carbonitrile;-   (2S,5S)-5-methyl-1-{N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo(3.1.1)hept-3-yl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5S)-1-{N-((5R,7S)-3-hydroxy-1-adamantyl)glycyl}-5-methylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-{N-(2-(3,4-dimethoxyphenyl)ethyl)glycyl}-5-methylpyrrolidine-2-carbonitrile;-   (2S,5S)-4,4-difluoro-5-methyl-1-((5S)-5-methyl-L-prolyl)pyrrolidine-2-carbonitrile;-   (2S,5S)-1-(N-isopropylglycyl)-5-methylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-L-isoleucyl-5-methylpyrrolidine-2-carbonitrile;-   (2S,5R)-5-methyl-1-{N-(2-(5-cyano-pyridin-2-ylamino)ethyl)glycyl}pyrrolidine-2-carbonitrile;-   (2S,5S)-5-methyl-1-((3S)-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)pyrrolidine-2-carbonitrile;-   (2S,5S)-1-(3-cyclopropyl-L-alanyl)-5-methylpyrrolidine-2-carbonitrile;-   (2S,5S)-5-methyl-1-D-prolylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-(N-2,3-dihydro-1H-inden-1-ylglycyl)-5-methylpyrrolidine-2-carbonitrile;-   (2S,5S)-5-methyl-1-L-valylpyrrolidine-2-carbonitrile;-   (2S,5S)-5-methyl-1-(4-methyl-L-leucyl)pyrrolidine-2-carbonitrile;-   (2S,5S)-1-(N-(4-trans    hydroxycyclohexyl)glycyl)-5-methylpyrrolidine-2-carbonitrile;-   (2S,5S)-1-(N-(tert-butyl)glycyl)-5-methylpyrrolidine-2-carbonitrile;-   (2S,5S)-5-methyl-1-((5S)-5-methyl-L-prolyl)pyrrolidine-2-carbonitrile;-   (2S,5S)-1-(3-cyclohexyl-L-alanyl)-5-methylpyrrolidine-2-carbonitrile;-   6-{[4-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-4-methylcyclohexyl]oxy}-N,N-dimethylnicotinamide;-   (1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-N-(pyridin-2-ylmethyl)cyclopentanecarboxamide;-   (1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-N-quinolin-2-ylcyclopentanecarboxamide;-   (2S,5R)-5-ethynyl-1-({[4-methyl-1-(5-nitropyridin-2-yl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile;-   (2S,5R)-5-ethynyl-1-[({4-methyl-1-[5-(methylsulfonyl)pyridin-2-yl]piperidin-4-yl}amino)acetyl]pyrrolidine-2-carbonitrile;-   methyl    (1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)cyclopentanecarboxylate;    and-   (2R,5S)-1-[(tert-butylamino)acetyl]pyrrolidine-2,5-dicarbonitrile.

The present compounds can exist as therapeutically acceptable salts. Theterm “therapeutically acceptable salt,” refers to salts or zwitterionsof the compounds which are water or oil-soluble or dispersible, suitablefor treatment of disorders without undue toxicity, irritation, andallergic response, commensurate with a reasonable benefit/risk ratio,and effective for their intended use. The salts can be prepared duringthe final isolation and purification of the compounds or separately byreacting an amino group of the compounds with a suitable acid.Representative salts include acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate,methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate,pivalate, propionate, succinate, tartrate, trichloroacetate,trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate,hydrochloric, hydrobromic, sulfuric, phosphoric, and the like. The aminogroups of the compounds can also be quaternized with alkyl chlorides,bromides, and iodides such as methyl, ethyl, propyl, isopropyl, butyl,lauryl, myristyl, stearyl, and the like. The present inventioncontemplates pharmaceutically acceptable salts formed at the nitrogen offormula (I) to which R₃ is attached.

Basic addition salts can be prepared during the final isolation andpurification of the present compounds by reaction of a carboxyl groupwith a suitable base such as the hydroxide, carbonate, or bicarbonate ofa metal cation such as lithium, sodium, potassium, calcium, magnesium,or aluminum, or an organic primary, secondary, or tertiary amine.Quaternary amine salts derived from methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine, tributlyamine,pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine, ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine, and the like, arecontemplated as being within the scope of the present invention.

The present compounds can also exist as therapeutically acceptableprodrugs. The term “therapeutically acceptable prodrug,” refers to thoseprodrugs or zwitterions which are suitable for use in contact with thetissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use. The term “prodrug,” refers tocompounds that are rapidly transformed in vivo to the parent compoundsof formula (I) for example, by hydrolysis in blood.

Asymmetric centers can exist in the present compounds. Individualstereoisomers of the compounds are prepared by synthesis from chiralstarting materials or by preparation of racemic mixtures and separationby conversion to a mixture of diastereomers followed by separation orrecrystallization, chromatographic techniques, or direct separation ofthe enantiomers on chiral chromatographic columns. Starting materials ofparticular stereochemistry are either commercially available or are madeby the methods described hereinbelow and resolved by techniqueswell-known in the art.

Geometric isomers can exist in the present compounds. The inventioncontemplates the various geometric isomers and mixtures thereofresulting from the disposal of substituents around a carbon-carbondouble bond, a cycloalkyl group, or a heterocycloalkyl group.Substituents around a carbon-carbon double bond are designated as beingof Z or E configuration and substituents around a cycloalkyl orheterocycloalkyl are designated as being of cis or trans configuration.

Therapeutic compositions of the present compounds comprise an effectiveamount of the same formulated with one or more therapeuticallyacceptable excipients. The term “therapeutically acceptable excipient,”as used herein, represents a non-toxic, solid, semi-solid or liquidfiller, diluent, encapsulating material, or formulation auxiliary of anytype. Examples of therapeutically acceptable excipients include sugars;cellulose and derivatives thereof; oils; glycols; solutions; buffering,coloring, releasing, coating, sweetening, flavoring, and perfumingagents; and the like. These therapeutic compositions can be administeredparenterally, intracisternally, orally, rectally, or intraperitoneally.

Liquid dosage forms for oral administration of the present compoundscomprise formulations of the same as emulsions, microemulsions,solutions, suspensions, syrups, and elixirs. In addition to thecompounds, the liquid dosage forms can contain diluents and/orsolubilizing or emulsifying agents. Besides inert diluents, the oralcompositions can include wetting, emulsifying, sweetening, flavoring,and perfuming agents.

Injectable preparations of the present compounds comprise sterile,injectable, aqueous and oleaginous solutions, suspensions or emulsions,any of which can be optionally formulated with parenterally acceptablediluents, dispersing, wetting, or suspending agents. These injectablepreparations can be sterilized by filtration through abacterial-retaining filter or formulated with sterilizing agents thatdissolve or disperse in the injectable media.

Inhibition of DPP-IV by the compounds of the present invention can bedelayed by using a liquid suspension of crystalline or amorphousmaterial with poor water solubility. The rate of absorption of thecompounds depends upon their rate of dissolution which, in turn, dependson their crystallinity. Delayed absorption of a parenterallyadministered compound can be accomplished by dissolving or suspendingthe compound in oil. Injectable depot forms of the compounds can also beprepared by microencapsulating the same in biodegradable polymers.Depending upon the ratio of compound to polymer and the nature of thepolymer employed, the rate of release can be controlled. Depotinjectable formulations are also prepared by entrapping the compounds inliposomes or microemulsions that are compatible with body tissues.

Solid dosage forms for oral administration of the present compoundsinclude capsules, tablets, pills, powders, and granules. In such forms,the compound is mixed with at least one inert, therapeuticallyacceptable excipient such as a carrier, filler, extender, disintegratingagent, solution retarding agent, wetting agent, absorbent, or lubricant.With capsules, tablets, and pills, the excipient can also containbuffering agents. Suppositories for rectal administration can beprepared by mixing the compounds with a suitable non-irritatingexcipient which is solid at ordinary temperature but fluid in therectum.

The present compounds can be micro-encapsulated with one or more of theexcipients discussed previously. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric and release-controlling. In these forms, thecompounds can be mixed with at least one inert diluent and canoptionally comprise tableting lubricants and aids. Capsules can alsooptionally contain opacifying agents that delay release of the compoundsin a desired part of the intestinal tract.

Transdermal patches have the added advantage of providing controlleddelivery of the present compounds to the body. Such dosage forms areprepared by dissolving or dispensing the compounds in the proper medium.Absorption enhancers can also be used to increase the flux of thecompounds across the skin, and the rate of absorption can be controlledby providing a rate controlling membrane or by dispersing the compoundsin a polymer matrix or gel.

Disorders that can be treated or prevented in a patient by administeringto the patient, a therapeutically effective amount of compound of thepresent invention in such an amount and for such time as is necessary toachieve the desired result. The term “therapeutically effective amount,”refers to a sufficient amount of a compound of formula (I) toeffectively ameliorate disorders by inhibiting DPP-IV at a reasonablebenefit/risk ratio applicable to any medical treatment. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; the activity of the compound employed;the specific composition employed; the age, body weight, general health,sex, and diet of the patient; the time of administration, route ofadministration, rate of excretion; the duration of the treatment; anddrugs used in combination or coincidental therapy.

The total daily dose of the compounds of the present invention necessaryto inhibit the action of DPP-IV in single or divided doses can be inamounts, for example, from about 0.01 mg/kg/day to about 50 mg/kg/daybody weight. In a more preferred range, compounds of the presentinvention inhibit the action of DPP-IV in a single or divided doses fromabout 0.1 mg/kg/day to about 25 mg/kg/day body weight. Single dosecompositions can contain such amounts or multiple doses thereof of thecompounds of the present invention to make up the daily dose. Ingeneral, treatment regimens comprise administration to a patient in needof such treatment from about 10 mg to about 1000 mg of the compounds perday in single or multiple doses.

Biological Data

Isolation of Rat DPP-IV

DPP-IV was purified to homogeneity (electrophoretic) from rat kidney asdescribed in Arch. Biochem. Biophy. 1995, 323, 148-154. Rat kidney (120g) was homogenized in 4 volumes of water and the homogenate centrifugedfor 15 minutes at 1000 g. The pH of the supernatant was adjusted to 3.9with 1M HCl and the enzyme solubilized by autolysis for 18 hours at 37°C. The pH of the supernatant collected after centrifugation was adjustedto 7.2 with 1M Trizma base and the enzyme was precipitated with(NH₄)₂SO₄ at 90% saturation (662 g solid ammonium sulfate per liter ofsolution). The solubilized precipitate was chromatographed on SephadexG-200 (1 m×5 cm) equilibrated with a 10 mM Tris-HCl buffer pH 7.5containing NaCl at a final concentration of 0.1 M and developed from thebottom. Fractions containing enzymatic activity were pooled,chromatographed on DE-52 (16×2.5 cm) equilibrated with 10 mM Tris-HCl,pH 7.5, and eluted with a 250-mL linear 0-0.4 M NaCl gradient preparedin 10 mM Tris-HCl. DPP-IV was then resolved from other brush borderpeptidases by chromatography on a phenyl Sepharose column (12×2 cm)equilibrated with 25% (NH₄)₂SO₄ at saturation (144 g ammonium sulfateper liter of 0.05 M Tris-HCl, pH 7.5). The enzyme was eluted in ahomogeneous form with a 200-mL linear gradient of 25-0% (NH₄)₂SO₄,prepared in 0.05 M Tris HCl buffer.

Human DPP-IV

Caco-2 cells were obtained from American Type Culture Collection (P.O.Box 3605, Manassas, Va.), cultured and maintained at 37° C. with 5% CO₂in low glucose DMEM media supplemented with 10% Fetal Bovine Serum andantibiotic/antimycotic. In preparation for making an extract, cells wereseeded at a density to achieve confluence within 7 days. The cells werecultured for an additional 14 days to allow for maximal DPPIVexpression. On the day of harvest, cells were washed once withDulbecco's PBS and solubilized in a 10 mM NaCl containing 50 mM TrisHCl, 0.5% Nonidet P40 and 0.3 ug/ml aprotinin a pH 8.0. The extract wasclarified by centrifugation at 35,000 g for 30 minutes at 4° C.

Inhibition Constant Determination for DPP-IV

DPP-IV activity was determined by measuring the rate of hydrolysis of asurrogate substrate Gly-Pro-7-amido-methylcoumarin (Gly-Pro-AMC,Catalogue #G-2761, Sigma, St. Louis, Mo.). The assay is carried out atroom temperature in black 96 well polypropylene or 32 compounds are madein DMSO and then diluted ten fold into water. 10 μL of 5 concentrationsof the compound of formula (I) (inhibitor) or 10% DMSO in water areadded to individual wells containing 80 μL of DPP-IV diluted in assaybuffer containing 25 mM HEPES (pH 7.5), 150 mM NaCl and 0.12 mg/mL BSA.After 10 minutes at room temperature, the reaction is initiated byadding 10 μL of either 280, 700, 1750, or 3500 μM Gly-Pro-AMC in water.The DPP-IV activity results in the formation of the fluorescent productamido-methylcoumarin (AMC) which is continuously monitored by excitationat 350 nm and measurement of fluorescent emission at 460 nm every 112seconds for 37 minutes using an appropriate plate reader. Thefluorescence at 460 nm is converted to nanomoles of AMC using a standardcurve and the initial rate of AMC formation is calculated. For eachconcentration of compound of formula (I) (inhibitor) or DMSO control,the initial rates are used to fit the rectangular hyperbola ofMichaelis-Menten by non-linear regression analysis (GraphPad SoftwarePrism 3.0). The ratio of the apparent Km/Vmax vs. inhibitorconcentration is plotted and the competitive Ki is calculated by linearregression to be the negative x-intercept. The uncompetitive Ki issimilarly calculated from the x-intercept of the plot of the reciprocalof the apparent Vmax versus the inhibitor concentration (Cornish-Bowden,A. 1995. Fundamentals of Enzyme Kinetics. Revised edition. PortlandPress, Ltd., London, U.K.).

The compounds of the present invention were found to inhibit DPP-IVinduced fluorescence with inhibitory constants in a range of about 0.014μM to about 7 μM. In a preferred range, the compounds of the presentinvention inhibited DPP-IV induced fluorescence with inhibitoryconstants in a range of about of about 0.014 μM to about 1 μM; and in amore preferred range, the compounds of the present invention inhibitedDPP-IV induced fluorescence with inhibitory constants in a range ofabout of about 0.014 μM to about 0.5 μM.

As inhibitors of DPP-IV action, the compounds of the present inventionare useful in treating disorders that are mediated by DPP-IV. Disordersthat are mediated by DPP-IV include diabetes, type II diabetes,hyperglycemia, Syndrome X, hyperinsulinemia and obesity. Therefore thecompounds of the present invention are useful in treating the disorderof diabetes, type II diabetes, hyperglycemia, Syndrome X,hyperinsulinemia and obesity.

Dipeptidyl-peptidase IV (DPP-IV, EC 3.4.14.5; CD26) is a post-prolinecleaving serine protease with significant homology to other alpha-betahydroxylases (e.g. prolyl oligopeptidase). DPP-IV is found throughoutthe body, both circulating in plasma and as a type II membrane proteinproduced by a variety of tissues, including kidney, liver and intestine.DPP-IV plays a role in the cleavage of specific substrates withaccessible amino-terminal Xaa-Pro- or Xaa-Ala-dipeptide sequences,resulting in their inactivation or alteration in their biologicalactivities. Important DPP-IV substrates include growth hormone releasinghormone, glucagon-like peptides or (GLP)-1 and 2, gastric inhibitorypolypeptide (GIP) and certain chemokines like RANTES (regulated onactivation, normal T cell expressed and secreted), stromal cell-derivedfactor, eotaxin, and macrophage-derived chemokine (Mentlein, R.Regulatory Peptides, 1999, 85, 9-24).

The DPP-IV substrate, glucagon-like peptide (GLP)-1, is released from Lcells in the distal small intestine and colon after oral ingestion ofnutrients. The active GLP-1 (7-36) amide is an incretin that increasesglucose stimulated insulin secretion (Drucker, D. J. Diabetes, 1998, 47,159-169). Other activities attributed to GLP-1 (7-36) amide includestimulation of insulin gene expression, trophic effects on pancreaticbeta cells, inhibition of glucagon secretion, promotion of satiety,inhibition of food intake, and slowing of gastric emptying (Drucker, D.J. Diabetes, 1998, 47, 159-169). These effects of GLP-1 (7-36) amidecontribute to glucose homeostasis and the normalization of blood glucoselevels in conditions of impaired glucose tolerance. In this regard,GLP-1 (7-36) amide has been demonstrated to reduce postprandial andfasting glycemia in patients with insulin-dependent andnon-insulin-dependent diabetes mellitus (Nauck, et al., Hormone Metab.Res. 2002, 29, 411-416; Gutniak et al., J. Internal Medicine, 2001, 250,81-87; Rauchman, et al., Diabetologia. 1997, 40, 205-11; Ahren, B.BioEssays 1998, 20, 642-51). GLP-1 based therapy has therapeuticpotential for the treatment of type 2 diabetes. However, active GLP-1(7-36) amide is rapidly converted to GLP-1 (9-36) amide by DPP-IVcleavage of the amino-terminal His-Ala-dipeptide of GLP-1 (7-36) amide(Mentlein, et al., Eur. J. Biochem. 1993, 214, 829-835). The resultingGLP-1 (9-36) amide is inactive and is an antagonist of the GLP-1receptor (Knudson, et al., Eur. J. Pharmacol. 1996, 318, 429-35). Theshort half-life of GLP-1 (7-36) amide in the circulation (1-1.5 minutes)makes it impractical as a therapeutic agent and has led to thedevelopment of alternative strategies to enhance the anti-diabetogenicactivity of GLP-1. One strategy is to increase the circulating half-lifeof GLP-1, by inhibiting DPP-IV activity (Deacon, et al., Diabetes. 1995,44 1126-31). Inhibition of DPP-IV in vivo increases the level ofcirculating GLP-1 (7-36) amide with a concomitant increase in itsinsulinotropic effect (Deacon, et al., Diabetes. 1998, 47, 764-9). ADPP-IV inhibitor has been demonstrated to improve glucose tolerance innon-insulin-dependent diabetes mellitus (Ahren, B., et al., DiabetesCare 2002, 25, 869-875). Therefore, the compounds of the presentinvention, including but not limited to those specified in the examplescan be used in the treatment of conditions caused by or associated withimpaired glucose tolerance including the prevention or treatment ofdiabetes, especially non-insulin-dependent diabetes mellitus,hyperglycemia, hyperinsulinemia and metabolic syndrome (Johannsson, etal., J. Endocrinol. Invest. 1999, 22(5 Suppl), 41-6).

Striking similarities exist between the metabolic syndrome (Syndrome X)and untreated growth hormone deficiency. Abdominal/visceral obesity andinsulin resistance characterize both syndromes (Reaven, G M, Physiol.Rev. 1995, 75, 473-86; Johansson, et al., Metabolism. 1995, 44,1126-29). Growth hormone favorably effects some of the perturbationsassociated with abdominal/visceral obesity, including reduction inabdominal/visceral obesity, improved insulin sensitivity and lipoproteinmetabolism and reduction in diastolic blood pressure (Barreto-Filho, etal., J. Clin. Endocrinol. Metab. 2002, 87(5), 2018-23; Colao et al., J.Clin. Endocrinol. Metab. 2002, 57(3), 1088-93; Gotherstrom, et al., JClin Endocrinol Metab. 2001, 86(10), 4657-65; Johannsson, et al., J.Endocrinol. Invest. 1999, 22(5 Suppl), 41-6; Johannsson, et al., J.Clin. Endocrinol. Metab. 1997, 82(3), 727-34).

For the treatment of diabetes or Syndrome X, compounds of the presentinvention may be used alone, or in combination with any existinganti-diabetic agent. Agents which may be used in combination with thecompounds of the present invention include, but are not limited toinsulin, an insulin analog such as mecasermin and the like, an insulinsecretagogue such as nateglinide and the like, a biguanide such asmetformin and the like, a sulfonylurea such as chlorpropamide,glipizide, glyburide, and the like, an insulin sensitizing agent such asa PPARγ agonist such as troglitazone, pioglitazone, rosiglitazone, andthe like, an α-glucosidase inhibitor such as acarbose, voglibose,miglitol and the like, an aldose reductase inhibitor such as zopolrestatand the like, a metiglinide such as repaglinide and the like, a glycogenphosphorylase inhibitor, GLP-1 or a mimetic of GLP-1 such as exendin-4,or other such anti-diabetic agents that are known to one skilled in theart. The ability of the compounds of the present invention to treatdiabetes, alone or in combination with another agent, can bedemonstrated according to the methods described by Zander, M.; Mustafa,T.; Toft-Nielsen, M.-B.; Madsbad, S.; Hoist, J. J. in Diabetes Care2001, 24, 120-125; or, according to the methods described herein.

DPP-IV-mediated proteolysis has been established as a major route ofgrowth hormone releasing hormone (GHRH) degradation and inactivation(Kubiak, et al., Drug Metab. Dispos. 1989, 17, 393-7). GHRH-derivativesthat are resistant to DPP-IV cleavage are more potent in increasingserum growth hormone levels when administered i.v. due to longerstability in vivo. DPP-IV inhibition would be predicted to increase GHRHlevels and thus scrum growth hormone levels. Therefore, the compounds ofthe present invention, including but not limited to those specified inthe examples can be used in the treatment of conditions associated withdeficiency in growth hormone including metabolic disorders (centralobesity, dyslipidemia), osteoporosis and frailty of aging.

Diabetic dyslipidemia is characterized by multiple lipoprotein defectsincluding moderately high serum levels of cholesterol and triglycerides,small LDL particles and low levels of HDL cholesterol. The dyslipidemiaassociated with non-insulin-dependent diabetes mellitus is improved inconjunction with improved diabetic condition following treatment withGLP-1 (Junti-Berggren, et al., Diabetes Care. 1996, 19, 1200-6). DPP-IVinhibition is predicted to increase the level of circulating GLP-1(7-36) amide and thereby would be effective in the treatment of diabeticdyslipidemia and associated complications. Therefore, the compounds ofthe present invention, including but not limited to those specified inthe examples can be used in the treatment hypercholesterolemia,hypertriglyceridemia and associated cardiovascular disease.

Parenteral injection of GLP-1 (7-36) amide in healthy men, obese men orpatients with non-insulin-dependent diabetes mellitus has been reportedto promote satiety and to suppress food intake (Flint, et al., J. Clin.Invest. 1998, 101, 515-520; Naslund, et al., Am. J. Clin. Nutr. 1998,68, 525-530; Gutzwiller, et al., Am. J. Physiol. 1999, 276, R1541-R1544.DPP-IV inhibition is predicted to increase the level of circulatingGLP-1 (7-36) amide and thereby increases satiety in obesity andnon-insulin-dependent diabetes mellitus. Therefore, the compounds of thepresent invention, including but not limited to those specified in theexamples can be used in the treatment of obesity.

For the treatment of obesity, compounds of the present invention may beused alone, or in combination with any existing anti-obesity agent asdescribed by Flint, A.; Raben, A.; Astrup, A.; Hoist, J. J. in J. Clin.Invest. 1998, 101, 515-520 or by Toft-Nielsen, M.-B.; Madsbad, S.;Hoist, J. J. in Diabetes Care 1999, 22, 1137-1143. Agents which may beused in combination with the compounds of the present invention include,but are not limited to fatty acid uptake inhibitors such as orlistat andthe like, monoamine reuptake inhibitors such as sibutramine and thelike, anorectic agents such as dexfenfluramine, bromocryptine, and thelike, sympathomimetics such as phentermine, phendimetrazine, mazindol,and the like, thyromimetic agents, or other such anti-obesity agentsthat are known to one skilled in the art.

DPP-IV is expressed on a fraction of resting T cells at low density butis strongly upregulated following T-cell activation. DPP-IV may haveimportant functions on T cells and in the immune system. Syntheticinhibitors of the enzymatic activity of CD26 have been shown to suppresscertain immune reactions in vitro and in vivo. In vitro recombinantsoluble DPP-IV enhances proliferative responses of peripheral bloodlymphocytes to stimulation with soluble tetanus toxoid antigen. Inaddition, the enhancing effect requires DPP-IV enzyme activity (Tanaka,et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3082-86; Tanaka, et al.,Proc. Natl. Acad. Sci. USA 1993, 90, 4583). Soluble DPP-IV up-regulatesthe expression of the costimulatory molecule CD86 on monocytes throughits dipeptidyl peptidase IV activity suggesting that soluble DPP-IVenhances T cell immune response to recall antigen via its direct effecton antigen presenting cells (Ohnuma, et al., J. Immunol. 2001, 167(12),6745-55). Consequently, DPP-IV inhibition would be predicted to suppresscertain immune responses and thus have therapeutic benefit in thetreatment of immunomodulatory diseases. Therefore, the compounds of thepresent invention, including but not limited to those specified in theexamples can be used in the treatment of rheumatoid arthritis, multiplesclerosis, scleraderma, chronic inflammatory bowel disease or syndromeand allograft rejection in transplantation.

Chemokine receptors, especially CCR5 and CXCR4, act as cofactors forHIV-1 entry into CD4+ cells and their corresponding ligands can suppressHIV entry and thus replication. The CXC chemokine, stromal cell derivedfactor-1 (SDF-1) is a chemokine for resting T-lymphocytes and monocytes.SDF-1 exists as two splice variants, SDF-1 alpha and SDF-1beta thatdiffer by four additional C-terminal residues in SDF-1 beta. Truncationof the N-terminal Lys-Pro-residues from both SDF-1 alpha and SDF-1 betaresults in the loss of their chemotactic and antiviral activities invitro (Ohtsuki, et al, FEBS Lett. 1998, 431, 236-40; Shioda, et al.,Proc. Natl. Acad. Sci. USA 1998 95(11), 6331-6; Proost, et al., FEBSLett. 1998, 432, 73-6). DPP-IV inactivates SDF-1 alpha as a ligand forCXCR4 that is a T cell chemotactic receptor as well as the majorco-receptor for T-tropic HIV-1 strains. DPP-IV inhibition would bepredicted to increase full-length SDF-1 levels and thereby suppressHIV-1 entry into CXCR4+ cells. Therefore, the compounds of the presentinvention, including but not limited to those specified in the examplescan be used in the treatment of HIV infection (AIDS).

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichtogether illustrate the methods by which the compounds of the inventionmay be prepared. Starting materials can be obtained from commercialsources or prepared by well-established literature methods known tothose of ordinary skill in the art. The synthesis of compounds offormula (I), wherein the groups R, R₁, R₂ and R₃ are as defined aboveunless otherwise noted below, are exemplified below.

As shown in Scheme 1, compounds of formula 1, which may either bepurchased directly or modified from commercially available startingmaterial through methods commonly known to those skilled in the art, maybe reacted with compounds of formula 2 (wherein P is a nitrogenprotecting group such as but not limited to tert-butyloxycarbonyl,benzyloxycarbonyl and acetyl) along with reagents such as but notlimited to 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride(EDCI) or 2-(1H-benzotriazol-1yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TBTU) and 4-dimethylaminopyridine (DMAP) in thepresence of a base such as but not limited to N-methylmorpholine ordiisopropyl ethyl amine in solvents such as but not limited todichloromethane to provide compounds of formula 3. Compounds of formula3 may be reacted with reagents known to deprotect the nitrogenprotecting group as known to those skilled in the art or demonstrated inGreene, T. W. and Wuts, G. M. “Protective groups in Organic Synthesis”,third ed. John Wiley & Sons, 1999, to provide compounds of formula 4,which are representative of compounds of formula (I).

Alternatively, compounds of formula 4 which are representative ofcompounds of formula (I) can also be synthesized as described in Scheme2. Compounds of formula 1 can be reacted with compounds of formula 5(where Y is either bromine or chlorine) in the presence of a base suchas, but not limited to, triethylamine or diisopropylethylamine insolvents such as but not limited to THF to provide compounds of formula6. Compounds of formula 6 can be reacted with amines of formula 7 insolvents such as, but not limited to, acetonitrile to provide compoundsof formula 4.

As shown in Scheme 3, compounds of formula 8 which are representative ofcompounds of formula (I) wherein R is alkoxycarbonyl can be modifiedthrough techniques known to those skilled in the art to providecompounds of formula 11 which are representative of compounds of formula(I) wherein R is cyano. Compounds of formula 8 may be reacted withreagents which will effect a hydrolysis of an alkoxycarbonyl group suchas, but not limited to, lithium hydroxide or sodium hydroxide in aqueousalcoholic solvents such as but not limited to aqueous methanol oraqueous ethanol to provide of formula 9. Compounds of formula 9 can bereacted with isobutylchloroformate, a base such as N-methylmorpholine inTHF at −15° C. for 20 minutes followed by the addition of ammonia indioxane to provide compounds of formula 10. Compounds of formula 10 canthen be reacted with phosphorous oxychloride, pyridine and imidazole at−35° C. or with trifluoracetic anhydride at 0° C. in a mixture of THFand DMF (1:1) to provide compounds of formula 11A. The nitrogenprotecting group of compounds of formula 11A can be removed usingconditions known to those skilled in the art to provide compounds offormula 11.

As shown in Scheme 4, compounds of formula 12 (wherein P is a nitrogenprotecting group as previously described) can be reacted withorganometallic reagents such as but not limited to 13 in solvents suchas but not limited to THF at temperatures between −20° C. and −40° C. toprovide compounds of formula 14. Compounds of formula 14 can beconverted to compounds of formula 15 through the deprotection of theamine protecting group using methods known to those skilled in the art.Compounds of formula 15 can be reduced by hydrogenolysis using 50-60 psiof hydrogen gas and palladium on carbon in solvents such as but notlimited to ethanol, methanol, or ethyl acetate or with a hydride sourcesuch as sodium borohydride to provide compounds of formula 16. Compoundsof formula 16 can be reacted according to the reaction conditionsoutlined in Scheme 1 or Scheme 2 to provide compounds of formula 8.Compounds of formula 8 can be reacted according to the reactionconditions outlined in Scheme 3 to provide compounds of formula 11 whichare representative of compounds of formula (I).

As shown in Scheme 5, compounds of formula 12 can be treated withreducing reagents such as lithium triethylborohydride in THF at −78° C.to selectively reduce the carbonyl functional group to the alcohol whichcan then be converted to the methyl ether upon treatment withpara-toluensulfonic acid in methanol to provide compounds of formula 18.Compounds of formula 18 can be reacted with bis-trimethylsilylacetylene,tin(IV)chloride and AlCl₃, in solvents such as but not limited todichloromethane to provide compounds of formula 19. Compounds of formula19 can be converted to compounds of formula 20 using conditions known tothose skilled in the art that will deprotect the amine protecting groupas previously mentioned in Scheme 1. Compounds of formula 20 can bereacted according to the conditions outlined in Scheme 1 or Scheme 2 toprovide compounds of formula 21 which can be further reacted accordingto the conditions outlined in Scheme 3 to provide compounds of formula22 which are representative of compounds of formula (I).

As shown in Scheme 6, compounds of formula 23 can be reacted with otheracetylene compounds under conditions described in Scheme 5 to providecompounds of formula 24 wherein R₄ is a member selected from the groupconsisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkylcarbonyl, alkylcarbonylalkyl, heterocycle, and heterocyclealkyl.Compounds of formula 24 can be treated under conditions known todeprotect nitrogen protecting groups as known to those skilled in theart or are described in Scheme 1 or Scheme 2 to provide compounds offormula 25. Compounds of formula 25 can be subjected to conditionsoutlined in Scheme 1 and 2 provide compounds of formula 26. Compounds offormula 26 can be subjected to conditions outlined in Scheme 3 toconvert the ethyl ester to the corresponding nitrile providing compoundsof formula 27 which are representative of compounds of formula (I).

As shown in Scheme 7, compounds of formula 28 may be converted tocompounds of formula 29 which are representative of compounds of formula(I). The alcohol functionality of 28 can be reacted with diethylazodicarboxylate and triphenylphosphine in THF followed byortho-nitrobenzenesulfonylhydrazine to provide compounds of formula 29.The protecting group of compound of formula 29 can be removed underconditions known to those skilled in the art.

As shown in Scheme 8, compounds of formula 22 can be converted tocompounds of formula 30 which are representative of compounds of formula(I) under an atmosphere of hydrogen in the presence of a catalyst suchas but not limited to palladium on barium sulfate poisoned withquinoline in a solvent such as but not limited to methanol or ethylacetate.

As shown in Scheme 9, compounds of formula 30 can be converted tocompounds of formula 31 which are representative of compounds of formula(I) under an atmosphere of oxygen in the presence of a catalyst ofpalladium chloride in solvents such as but not limited to THF ordioxane.

Compounds of the present invention may contain an R₃ group that consistsof an amino-piperidine ring as described by formula 34 which are withinthe scope of compounds of formula 7. Such rings can be treated withcompounds of general formula 6 according to conditions described inScheme 2 to provide compounds of general formula 4 wherein R₃ consistsof a piperidine ring. Scheme 10 describes the synthesis of compounds offormula 34 (or 7) wherein R₃ consists of a substituted piperidine ring.Amino-piperidine rings of formula 32, wherein P is an amino protectinggroup such as but not limited to tert-butyloxycarbonyl, can be treatedwith a halogen-substituted heterocycle or an aryl halide of formulaR₈—Y, wherein R₈ consists of a heterocycle or aryl moiety and Y consistsof a halogen in the presence of a base such as diisopropylethylamine ina solvent such as dioxane with heating between 50° C. and 200° C. fromeither a convention heat source or from a microwave source undermicrowave conditions to provide compounds of formula 33. Examples ofR₈—Y include but are not limited to a 2-chloropyridine,2-chloropyrimidine and chlorobenzene. Alternatively, compounds offormula 32 and halogen-substituted heterocycle or aryl halides offormula R₈—Y, may be coupled using a palladium catalyst such asPd₂(dba)₃ with an appropriate ligand such as XANTHPOS in the presence ofa base such as cesium carbonate in a solvent such as dioxane withheating to approximately 100° C. The protecting group can then beremoved using conditions known to those skilled in the art to provide acompound of formula 7 which can be treated with compounds of formula 6as described in Scheme 2 to provide compound of formula 4 wherein R₃ isa piperidine ring

Alternatively, compound of formula 32 may be reacted with an acidchloride of formula R₈C(O)Cl, wherein R₈ is defined above, in thepresence of a base such as triethylamine in a solvent such asdichloromethane or tetrahydrofuran to supply a compound of formula 33wherein R₈C(O)— is an acyl group appended to the piperidine nitrogen.Alternatively, an acid of formula R₈C(O)OH, may be coupled to thepiperidine using a coupling reagent such as but not limited to acarbodiimide or uronium salt with additives such as HOBT or DMAP. Theprotecting group may be removed to furnish piperidines of formula 34which can be treated with compounds of formula 6 as described in Scheme2 to provide compounds of formula 4 wherein R₃ is a piperidine.

Compounds of the present invention may also contain an R₃ group thatconsists of a cyclohexyl ring that is substituted with an ether group(R₉O—) as described by formula 36. Cyclohexyl ethers of formula 36 aresynthesized from compounds of formula 35 by treatment with aryl halidesor halogen-substituted aromatic heterocycles such as chloropyridines orchloropyrimidines. The appropriate 4-aminocyclohexanol of formula 35 istreated with a base such as sodium hydride in a solvent such asdimethylformamide at approximately 0° C., followed by the addition of anaryl halide or halogen-substituted aromatic heterocycle. The reactionmixture may be heated to approximately 60° C. until complete. Furtherderivitization of functional groups on either the heterocycle or arylring may be accomplished by one skilled in the art to provide compoundsof formula 36. Such transformations may require appropriate protectionand deprotection of the amine moiety. Compounds of formula 36 can thenbe treated with compounds of formula 6 as described in Scheme 2 toprovide compounds of formula 4 where R₃ is a substituted cyclohexylring.

Compounds of the present invention may contain mono or difluoropyrrolidines as represented by compound of formula 43 in Scheme 12 arealso within the scope of the compounds of formula 1 shown in Scheme 1.An amino acid of formula 37 wherein P is a nitrogen protecting group andR₁₂ is an alkyl group, may be treated with a fumarate of formula 38 inthe presence of a base such as sodium hydride in solvents such astoluene at room temperature to provide a pyrrolidine of formula 39.Compounds of formula 39 can be subjected to conditions known to cleaveester groups to provide the beta-keto dicarboxylic acid which can besubjected to conditions known to decarboxylate beta-keto carboxylicacids to form a monocarboxylic acid as described by compounds of formula40. Esterification of the carboxylic acid in compounds of formula 40using conditions known to those skilled in the art will providecompounds of formula 41. Treatment of compounds of formula 41 withN,N-diethylaminosulfur trifluoride (DAST) in dichloromethane at −78° C.produces the fluorinated pyrrolidines of compounds of formula 42.Removal of the protecting group yields the pyrrolidines described by thecompounds of formula 43. Compounds of formula 43 which are within thescope of compounds of formula 1 can be treated according to theconditions described in Scheme 1 or 2 to provide compounds of formula 4which contain a difluoropyrrolidine.

The compounds of the present invention may also contain a2,5-dicyanopyrrolidine as represented by the compounds of formula 49 inScheme 13. Compounds of formula 44 may be prepared by thermalcyclization of compounds of formula 43 in the presence of benzyl amine.The benzyl group of compounds of formula 44 may be removed by treatmentwith an atmosphere of hydrogen in the presence of a catalyst such as butnot limited to 5% palladium on carbon in various solvents or by othermethods known to one skilled in the art or as described in Greene, T. W.and Wuts, G. M. “Protective groups in Organic Synthesis”, third ed. JohnWiley & Sons, 1999 to provide compounds of formula 45. The treatment ofcompounds of formula 45 with a compound of formula 2 according toconditions outlined in Scheme 1 will provide compounds of formula 47.The treatment of compounds of formula 47 which contain ester groupsaccording to the conditions outlined in Scheme 3 will provide thecompounds of formula 48 that contain nitrile groups. The removal of thenitrogen protecting group P of compounds of formula 48 can be effectedby treatment with reagents known to deprotect the nitrogen protectinggroup as known to those skilled in the art or demonstrated in Greene, T.W. and Wuts, G. M. “Protective groups in Organic Synthesis”, third ed.John Wiley & Sons, 1999, to provide compounds of formula 49 which arerepresentative of compounds of the present invention.

The compounds and processes of the present invention will be betterunderstood by reference to the following examples, which are intended asan illustration of and not a limitation upon the scope of the invention.Further, all citations herein are incorporated by reference.

Compounds of the invention were named by ACD/ChemSketch version 5.01(developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada)or were given names consistent with ACD nomenclature.

EXAMPLES Example 1(2S,5R)-5-ethynyl-1-L-leucylpyrrolidine-2-carbonitrile Example 1Adimethyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate

To a cold (−78° C.) solution of methyl(S)-(+)-2-pyrrolidone-5-carboxylate (4.80 grams, 33.5 mmol) intetrahydrofuran (90 mL) was added a solution of lithiumbis(trimethylsilyl)amide (1 M solution in hexanes, 40.0 mL, 40.0 mmol)dropwise via syringe over 15 minutes; then methyl chloroformate (2.90mL, 36.9 mmol) was added dropwise via syringe over 5 minutes. Theresulting slurry was stirred at −78° C. for 1 hour after which thereaction was quenched with 1 M HCl (50 mL). The mixture was allowed tocome to room temperature, concentrated under reduced pressure and theresidue partitioned between ethyl acetate (200 mL) and 1 M HCl (200 mL).The aqueous layer was extracted with ethyl acetate (2×200 mL) and thecombined organic layers were dried (sodium sulfate), filtered, andconcentrated to provide the titled compound. MS (DCI/NH₃) m/e 202(M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ ppm 4.70 (dd, 1H), 3.88 (s, 3H), 3.80(s, 3H), 2.74-2.30 (m, 3H), 2.15-2.05 (m, 1H).

Example 1B dimethyl(2S)-5-methoxypyrrolidine-1,2-dicarboxylate

To a cold solution (−78° C.) ofdimethyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate (5.80 g, 28.8 mmol) intetrahydrofuran (100 mL) was added a solution of lithiumtriethylborohydride (1 M in THF, 35 mL, 35 mmol) dropwise via syringeover 10 minutes. The resulting solution was stirred at −78° C. for 30minutes, quenched by the careful addition of saturated sodiumbicarbonate solution (50 mL), allowed to warm to 0° C. and 30% hydrogenperoxide (6 mL) was carefully added dropwise. The mixture was stirredfor 30 minutes at room temperature, reduced in volume under reducedpressure, and diluted with ethyl acetate (300 mL) and brine (200 mL).The milky aqueous layer was separated and further extracted with ethylacetate (2×300 mL). The combined organic layers were dried (sodiumsulfate), filtered, and concentrated to a light yellow oil. The yellowoil was taken up in methanol (50 mL) containing para-toluenesulfonicacid hydrate (487 mg, 2.6 mmol) and stirred at room temperature for 16hours. The reaction was diluted with aqueous sodium bicarbonate solution(40 mL), the volatile solvents were removed under reduced pressure andthe residue partitioned between ethyl acetate (200 mL) and brine (200mL). The aqueous layer was further extracted with ethyl acetate (200mL), the combined organic layers were dried (sodium sulfate), filtered,and concentrated to an oil which was chromatographed on a Biotage 40Mwith 60% hexane/40% ethyl acetate to provide the titled compound as amixture of diastereomers. (mixture of amide bond rotomers) ¹H NMR (300MHz, CDCl₃): δ ppm 5.37 (d, 1H), 5.33 (dd, 1H), 5.24 (d, 1H), 5.18 (dd,1H), 4.44-4.31 (m, 2H), 3.76 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.42(s, 3H), 3.34 (s, 3H).

Example 1C and 1Ddimethyl(2S,5R)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylateand dimethyl(2S,5S)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate

To a cold −45° C. solution ofdimethyl(2S)-5-methoxypyrrolidine-1,2-dicarboxylate (3.30 g, 15.20 mmol)and bistrimethylsilylacetylene (5.20 g, 30.4 mmol, 2.0 equiv) inmethylene chloride (45 mL) was added a solution of tin (IV) chloride (1M in methylene chloride, 20.0 mL, 20.0 mmol, 1.3 equiv) dropwise viasyringe over 15 minutes. To the dark yellow solution was added solidaluminum chloride (2.77 g, 20.8 mmol, 1.4 equiv) in one portion. Theresulting mixture was allowed to warm to room temperature and stirred atroom temperature for 48 hours. The reaction mixture was carefully pouredinto aqueous sodium bicarbonate solution (100 mL) with ice cooling. Awhite precipitate forms and 1 M HCl (ca. 50 mL) was added until thesolids dissolved. This mixture was extracted with ethyl acetate (2×200mL). The combined organic layers were filtered, dried (sodium sulfate),filtered, and concentrated. The residue was chromatographed on a Biotageflash 40 M eluting with 70% hexane/30% ethyl acetate to afford(2S,5S)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (transcompound Rf of 0.3 in 70% hexane/30% ethyl acetate) and dimethyl(2S,5R)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (ciscompound Rf of 0.2 in 70% hexane/30% ethyl acetate). Data for example1D: MS (DCI/NH₃) m/c 284 (M+H)⁺; The compound exists as a mixture ofrotomers. ¹H NMR (300 MHz, CDCl₃): δ ppm 4.60 (d, 1H), 4.51 (d, 1H),4.30 (d, 1H), 4.24 (d, 1H), 3.62 (s, 3H), 3.59 (s, 3H), 3.57 (s, 3H),3.54 (s, 3H), 2.40-2.28 (m, 2H), 2.11-2.04 (m, 2H), 1.90-1.81 (m, 4H),0.0 (s, 18H). Data for example 1C: MS (DCI/NH₃) m/e 284 (M+H)⁺; ¹H NMR(300 MHz, CDCl₃): δ ppm 4.55-4.40 (m, 1H), 4.20-4.15 (m, 1H), 3.59 (s,6H), 2.15-1.89 (m, 4H), 0.00 (s, 9H).

Example 1E methyl (5R)-5-((trimethylsilyl)ethynyl)-L-prolinate

A solution ofdimethyl(2S,5R)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate(5.43 g, 19.16 mmol) and iodotrimethylsilane (3 mL, 28.74 mmol) inchloroform (100 mL) was heated to 65° C. for 3 hours, was cooled to roomtemperature, concentrated under reduced pressure and flashchromatographed with 35% ethyl acetate/65% hexane to provide the titledcompound. MS (DCI/NH₃) m/e 226 (M+H)⁺.

Example 1F methylN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-((trimethylsilyl)ethynyl)-L-prolinate

To a solution of methyl (5R)-5-((trimethylsilyl)ethynyl)-L-prolinate(1.6 grams, 7.48 mmol), dimethylaminopyridine (913 mg, 7.48 mmol),N-methylmorpholine (1.23 mL, 11.22 mmol), andN-(tert-butoxycabonyl)-L-leucine monohydrate (2.24 g, 8.98 mmol) indichloromethane (30 mL) at room temperature was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.72 g,8.98 mmol). The resulting mixture was stirred 16 hours at roomtemperature, and partitioned between ethyl acetate (200 mL) and 1 MHO(200 mL). The aqueous layer was further extracted with ethyl acetate(200 mL). The combined organic layers were dried (sodium sulfate),filtered, and concentrated. The residue was chromatographed with aBiotage 40 M cartridge with 40% ethyl acetate/hexane provide the titledcompound. MS (DCI/NH₃) m/e 439 (M+H)⁺.

Example 1G N-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-proline

To a solution of methylN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-((trimethylsilyl)ethynyl)-L-prolinate(1.24 g, 2.83 mmol) in dioxane (12 mL) at room temperature was added asolution of 2 M lithium hydroxide (3 mL, 6.0 mmol). The resultingmixture was stirred at room temperature for 6 hours. The reaction wasdiluted with 1 M HCl solution (50 mL), and the aqueous mixture wasextracted with ethyl acetate (3×50 mL). The combined organic layers weredried (sodium sulfate), filtered, and concentrated to provide the titledcompound.

Example 1H N-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-prolinamide

To a cold (0° C.) solution ofN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-proline (2.83 mmol)and N-methyl morpholine (0.39 mL, 3.50 mmol) in THF (15 mL) was addedisobutyl chloroformate (0.42 mL, 3.25 mmol). The resulting cloudy whitemixture was stirred at 0° C. for 30 minutes followed by the addition ofa solution of ammonia (0.5 M in dioxane, 10.0 mL, 5.0 mmol). Thesolution was allowed to warm to room temperature and stirred for 16hours. The reaction mixture was diluted by the addition of 1 M HCl (100mL), and extracted with ethyl acetate (3×100 mL). The combined organiclayers were dried (sodium sulfate), filtered, and concentrated toprovide the titled compound.

Example 1IN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-pyrrolidine-2-carbonitrile

To a cold solution (−40° C.) ofN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-prolinamide (1.07 g,3.05 mmol) and imidazole (208 mg, 3.05 mmol) in pyridine (15 mL) wasadded POCl₃ (0.57 mL, 6.10 mmol) via syringe. The resulting mixture wasstirred, maintaining the temperature below −20° C., for 1 hour followedby the addition of 1 M HCl (100 mL). The aqueous mixture was extractedwith ethyl acetate (3×100 mL), and the combined organic layers weredried (sodium sulfate), filtered, concentrated and chromatographed with30% ethyl acetate/hexane to provide the titled compound. MS (DCI/NH₃)m/c 334 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃): δ ppm 5.15 (t, 1H), 4.95 (d,1H), 4.71 (t, 1H), 4.53 (ddd, 1H), 2.50 (d, 1H), 2.50-2.28 (m, 4H),1.75-1.57 (m, 3H).

Example 1 (2S,5R)-5-ethynyl-1-L-leucylpyrrolidine-2-carbonitrilehydrochloride

To a solution ofN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-pyrrolidine-2-carbonitrile(250 mg) in ether (1 mL) was added 4 M HCl in dioxane (2 mL). Theresulting mixture was stirred at room temperature for 5 hours and thesolvents removed under reduced pressure. The white solid was trituratedwith ether to provide the titled compound. MS (DCI/NH₃) m/e 234 (M+H)⁺;¹H NMR (300 MHz, MeOH-d₄): δ ppm 5.11 (d, 1H), 4.82 (m, 1H), 4.42 (dd,1H), 3.19 (d, 1H), 2.58-2.56 (m, 1H), 2.49-2.24 (m, 3H), 2.05-1.95 (m,1H), 1.87-1.81 (m, 2H), 1.08 (d, 3H), 1.04 (d, 3H).

Example 2(2S,5R)-5-ethynyl-1-((3S)-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)pyrrolidine-2-carbonitrilehydrochloride

Example 2 was prepared using the same procedures as described forExample 1 substituting(3S)-2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid for N-(t-butoxycarbonyl)-L-leucine monohydrate in the stepdescribed in example 1F. MS (DCI/NH₃) m/e 280 (M+H)⁺; ¹H NMR (300 MHz,MeOH-d₄): δ ppm 7.33-7.26 (m, 4H), 5.18 (m, 1H), 4.80 (dd, 1H), 4.49 (m,2H), 3.75 (m, 1H), 3.30-3.19 (m, 2H), 2.57-2.23 (m, 4H).

Example 3(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-ethynylpyrrolidine-2-carbonitrileExample 3A methyl(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-((trimethylsilyl)ethynyl)-L-prolinate

To a stirred solution of methyl(5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (1.2 g, 5.32 mmol) indichloromethane (30 mL) at ambient temperature under nitrogen was added4-dimethylamino pyridine (0.65 g, 5.32 mmol), 4-methylmorpholine (0.9mL, 7.98 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl carbodiimidehydrochloride (1.22 g, 6.39 mmol), and(2S)-((tert-butoxycarbonyl)amino)(cyclopentyl)acetic aciddicyclohexylamine salt (1.55 g, 6.39 mmol). The reaction mixture wasstirred at room temperature for 16 hours, diluted with ethyl acetate andwashed with 1 M HCl. The aqueous layer was further extracted with ethylacetate (2×) and the combined ethyl acetate layers were dried (Na₂SO₄)and evaporated. The residue was purified by flash chromatography 30%ethyl acetate/hexane to provide the titled compound. MS (CI) m/e 451(M+H)⁺.

Example 3B(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-proline

To a stirred solution of methyl(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-((trimethylsilyl)ethynyl)-L-prolinate(1.65 g, 3.66 mmol) in MeOH (10 mL) and H₂O (10 mL) at room temperaturewas added LiOH.H₂O (0.23 g, 5.49 mmol). The reaction mixture was stirredat room temperature for 16 hours and concentrated under reducedpressure. The residue was taken up in water and extracted with diethylether (2×). The aqueous layer was acidified to pH˜4 by adding 4% KHSO₄dropwise. The clear solution was extracted with ethyl acetate (3×) andthe combined ethyl acetate layers were washed with brine, dried(Na₂SO₄), filtered and concentrated under reduced pressure to providethe titled compound. MS (CI) m/e 365 (M+H)⁺.

Example 3C(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-prolinamide

To a stirred solution of(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-proline(1.28 g, 3.38 mmol) in THF (25 mL) at −15° C. under nitrogen, was added4-methylmorpholine (0.44 mL, 4.05 mmol), and isobutylchloroformate (0.5mL, 3.72 mmol) over 2 minutes. The reaction mixture was stirred at −15°C. under nitrogen for 30 minutes, and a solution of 0.5 M NH₃ in dioxane(34 mL, 16.90 mmol) was added. The reaction mixture diluted with water,the pH adjusted to 4 by the addition of 4% KHSO₄ and extracted withethyl acetate (3×). The combined extracts were washed with brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified by flashcolumn chromatography (5% MeOH/CH₂Cl₂) to provide the titled compound.MS (CI) m/c 364 (M+H)⁺.

Example 3D(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-pyrrolidine-2-carbonitrile

Trifluoroacetic anhydride (0.086 mL, 0.605 mmol), was added dropwise toa stirred ice-cooled solution of(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-prolinamide(200 mg, 0.55 mmol) in anhydrous dioxane (7 mL) and anhydrous pyridine(0.089 mL, 1.1 mmol) at such a rate that the temperature was kept below5° C. The reaction mixture was allowed to warm to room temperature andstirred for 16 hours. Tee was added to the residue, the solid productwas collected by filtration and washed with water. Purification by flashchromatography (30% ethyl acetate/hexane) provided the titled compound.MS (CI) m/e 346 (M+H)⁺.

Example 3E(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-ethynylpyrrolidine-2-carbonitrilehydrochloride

(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-pyrrolidine-2-carbonitrile(0.03 mg, 0.087 mmol), and 4 MHO in dioxane (0.15 mL, 0.6 mmol) werestirred at room temperature for 2 hours and evaporated under reducedpressure. Diethyl ether was added to the residue, and the formedprecipitate filtered. The solid was washed with diethyl ether (3×15 mL).The precipitate was dried in vacuo to provide the titled compound. MS(CI) m/z 246 (M+H)⁺; ¹H NMR (300 MHz, MeOH-d₄): 5 ppm 5.05 (m, 1H), 4.8(t, 1H), 4.3 (d, 1H) 3.19 (d, 1H), 2.4-2.68 (m, 3H), 2.2-2.28 (m, 2H),1.4-1.9 (m, 8H).

Example 4(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-vinylpyrrolidine-2-carbonitrilehydrochloride Example 4A tert-butyl(1S)-2-((2S,5R)-2-cyano-5-vinylpyrrolidin-1-yl)-1-cyclopentyl-2-oxoethylcarbamate

(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-pyrrolidine-2-carbonitrile(60 mg) was stirred under hydrogen (60 psi) at room temperature for 7minutes in a mixture of quinoline (66 uL) and ethyl acetate (6 mL) using5% Pd/BaSO₄ (24 mg). The mixture was filtered and the filtrateconcentrated under reduced pressure. Purification by flash columnchromatography with 20% ethyl acetate/hexane to provide the titledcompound. MS (CI) m/e 348 (M+H)⁺.

Example 4(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-vinylpyrrolidine-2-carbonitrilehydrochloride

Example 4 was prepared according to the procedure for Example 3Esubstituting tert-butyl(1S)-2-((2S,5R)-2-cyano-5-vinylpyrrolidin-1-yl)-1-cyclopentyl-2-oxoethylcarbamatefor(5R)-1-{(2S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylethanoyl}-5-ethynyl-L-pyrrolidine-2-carbonitrile.MS (CI) m/e 248 (M+H)⁺; ¹H NMR (300 MHz, MeOH-d₄): δ ppm 5.98-6.09 (m,1H), 5.3-5.39 (m, 2H), 4.7-4.8 (m, 1H), 4.1 (d, 1H), 2.38-2.49 (m, 2H),2.18-2.33 (m, 2H), 1.96-2.02 (m, 2H), 1.58-1.83 (m, 6H), 1.3-1.47 (m,2H).

Example 5(2S,5R)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-ethynylpyrrolidine-2-carbonitrilehydrochloride

Example 5 was prepared according to the procedures for Example 1F-Jsubstituting N-(t-butoxycarbonyl)-(2S)-amino(cyclohexy)acetic acid forN-(t-butoxycarbonyl)-L-leucine monohydrate in the step described inExample 1F. MS (CI) m/e 260 (M+H)⁺; ¹H NMR (300 MHz, MeOH-d₄): δ ppm5.58 (m, 1H), 5.0 (t, 1H), 4.24 (d, 1H), 3.2 (d, 1H), 2.3-2.42 (m, 3H),1.8-1.84 (m, 2H), 1.12-1.4 (m, 10H).

Example 6 (2S,5S)-5-ethyl-1-L-leucylpyrrolidine-2-carbonitrile Example6A ethyl (2S)-2-((tert-butoxycarbonyl)amino)-5-oxoheptanoate

Ethyl N-Boc (S)-pyroglutamate (2.33 g, 9.06 mmol, prepared as describedin: (a) St-Denis, Y., Augelli-Szafran, C. E.; Bachand, B.; Berryman, K.A.; DiMaio, J.; Doherty, A. M.; Edmunds, J. J.; Leblond, L.; Levesque,S.; Narasimhan, L. S.; Penvose-Yi, J. R.; Rubin, J. R.; Tarazi, M.;Winocour, P. D.; Siddiqui, M. A. Biorg. Med. Chem. Lett. 1998, 8,3193-3198. (b) Jain, R. Org. Prep. Procd. Intl. 2001, 33, 405-409.) wasdissolved in THF (6 mL) and the mixture was cooled to −40° C. Ethylmagnesiumbromide solution (1.0 M in THF, 10.84 mL, 10.84 mmol) was addedslowly via syringe, and the mixture was stirred cold for 2 hours. Thenthe reaction flask was placed in a freezer (approx −20° C.) for 16hours, the reaction was allowed to warm to room temperature and aqueousNH₄Cl and 1 N HCl were added. The mixture was extracted with ethylacetate (3×). The combined organic extracts were dried (Na₂SO₄),filtered, concentrated and purified by flash chromatography (30% ethylacetate/hexane) to provide the titled compound. MS (ESI) m/z 288 (M+H)⁺,310 (M+Na)⁺.

Example 6B ethyl (2S)-5-ethyl-3,4-dihydro-2H-pyrrole-2-carboxylate

Ethyl (2S)-2-((tert-butoxycarbonyl)amino)-5-oxoheptanoate andtrifluoroacetic acid (3 mL) were stirred in dichloromethane (3 mL) atroom temperature for 3 hours. The mixture was concentrated under reducedpressure to provide the titled compound. MS (ESI) m/z 170 (M+H)⁺.

Example 6C ethyl (5S)-5-ethyl-L-prolinate

Ethyl (2S)-5-ethyl-3,4-dihydro-2H-pyrrole-2-carboxylate dissolved inethanol (32 mL) was stirred with 0.30 g of 10% Pd/C and under hydrogen(60 psi) for 16 hours. The catalyst was removed by filtration, and thefiltrate was concentrated under reduced pressure to provide the titledcompound. MS (CI) m/z 172 (M+H)⁺.

Example 6D ethylN-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-prolinate

A solution of ethyl (5S)-5-ethyl-L-prolinate (2.5 mmol),2-(1H-benzotriazol-1yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(1.00 g, 3.13 mmol) and N-(tert-butoxycarbonyl)-L-leucine hydrate (0.779g, 3.12 mmol) were mixed in 4 mL of dimethylformamide. Triethylamine(approx 1.1 mL) was added until the pH reached about 6 (wet pH paper).After stirring for 16 hours, the mixture was concentrated under reducedpressure and the residue partitioned between 1 N HCl and ethyl acetate.The organic layer was washed with saturated NaHCO₃, dried (Na₂SO₄),filtered, concentrated under reduced pressure and purified by flashchromatography (30% to 50% ethyl acetate/hexane) to provide the titledcompound. MS (ESI) m/z 385 (M+H)⁺.

Example 6E N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-proline

Ethyl N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-prolinate (0.965g, 2.5 mmol) was dissolved in 3 mL of ethanol. The resultant solutionwas treated with 1.2 M LiOH solution (3.8 mL, 4.52 mmol) at roomtemperature. After 4 hours, the volatiles were removed under reducedpressure, and 1 N HCl was added. The mixture was extracted with ethylacetate (3×), and the combined organics were washed with brine, dried(Na₂SO₄), filtered and concentrated under reduced pressure to providethe titled compound. MS (ESI) m/z 357 (M+H)⁺.

Example 6F N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-prolinamide

N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-proline was mixed withtriethylamine (0.426 mL, 3.25 mmol) in THF (4 mL) and cooled to 0° C.followed by the addition of ethyl chloroformate (0.287 mL, 3.0 mmol).After 20 minutes, 0.5 M ammonia in dioxane (6 mL) was added. After 4hours, the mixture was concentrated, and the residue was partitionedbetween 1 N HCl and ethyl acetate. The organic extracts were washed withsaturated NaHCO₃, dried (Na₂SO₄), filtered, concentrated under reducedpressure and purified by flash chromatography (80% to 100% ethylacetate/hexane) to provide the titled compound. MS (ESI) m/z 356 (M+H)⁺.

Example 6GN-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-pyrrolidine-2-carbonitrile

N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-prolinamide (0.392 g,1.10 mmol) and imidazole (0.082 g, 1.21 mmol) were mixed in pyridine (4mL) and cooled to −35° C. followed by addition of POCl₃ (0.206 mL, 2.20mmol). After 1 hour, aqueous NH₄Cl solution was added, and the mixturewas concentrated under reduced pressure. 1 N HCl was added to theresidue, and the mixture was extracted with ethyl acetate (3×). Thecombined organic extracts were washed with 1 N HCl and brine, dried(Na₂SO₄), and concentrated under reduced pressure to provide the titledcompound. MS (ESI) m/z 338 (M+H)⁺. NOE from ROESY spectrum confirmed thecis-relationship between 2-cyano and 5-ethyl groups.

Example 6 (2S,5S)-5-ethyl-1-L-leucylpyrrolidine-2-carbonitriletrifluoroacetate

N-(tert-butoxycarbonyl)-L-leucyl-(5S)-5-ethyl-L-pyrrolidine-2-carbonitrile(299 mg) was mixed with 2 mL each of dichlormethane and trifluoroaceticacid at room temperature. After 3 hours, the volatiles were removedunder reduced pressure to provide the titled compound as thetrifluoroacetic acid salt. ¹H NMR (400 MHz, CDCl₃) δ 4.76 (t, 1H, J=8.0Hz), 4.27 (d, 1H, J=8.6 Hz), 4.04 (s, 1H), 2.26-2.38 (m, 2H), 1.87-2.05(m, 4H), 1.66 (m, 3H), 1.31 (m, 1H), 0.96-1.02 (m, 9H); MS (ESI) m/z 238(M+H)⁺.

Example 7(2S,5S)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-ethylpyrrolidine-2-carbonitriletrifluoroacetate

The titled compound was prepared according to procedure described inExample 6 by substituting N-(tert-butoxycarbonyl)-L-leucine hydrate withN-Boc-L-cyclohexylglycine in step 6D. ¹H NMR (400 MHz, MeOH-d₄) δ 5.09and 4.16 (m, 1H), 4.83 (t, 1H J=8.2 Hz), 4.00 (t, 1H, J=7.4 Hz), 2.48(m, 1H), 2.30 (m, 2H), 2.08 (m, 2H), 1.85 (m, 4H), 1.71 (m, 3H),1.17-1.33 (m, 5H), 1.02 and 0.95 (t, 3H, J=7.5 Hz); ¹³C NMR (MeOH-d₄,100 MHz) δ 119.7 and 119.9 ppm for CN group; MS (ESI) m/z 264 (M+H)⁺.

Example 8(2S,5R)-1-{N-((1R,2R,4S)-bicyclo(2.2.1)hept-2-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrileExample 8A methyl(5R)-1-(chloroacetyl)-5-((trimethylsilyl)ethynyl)-L-prolinate

To a stirred solution of methyl(5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (2.76 g, 12.2 mmol) andtriethylamine (2.13 mL, 15.3 mmol) in dry tetrahydrofuran (50 mL) at 0°C. was gradually added a solution of chloroacetyl chloride (0.97 mL,12.2 mmol) in dry tetrahydrofuran (10 mL). After stirring at roomtemperature for 2 hours, the mixture was filtered. The solid cake waswashed with THF, and the filtrate and washings were combined, dried oversodium sulfate and concentrated under reduced pressure. The residuetaken up in toluene and concentrated to dryness under reduced pressureto provide the titled compound. MS (CI) m/z 302 (M+1)⁺.

Example 8B (5R)-1-(chloroacetyl)-5-ethynyl-L-proline

To a stirred solution of methyl(5R)-1-(chloroacetyl)-5-((trimethylsilyl)ethynyl)-L-prolinate (3.69 g,12.2 mmol) in MeOH (24 mL) and H₂O (24 mL) at room temperature was addedLiOH•H₂O (0.8 g, 18 mmol). The reaction mixture was stirred at ambienttemperature overnight and concentrated under reduced pressure. Theresidue was taken up in water and extracted with diethyl ether (2×). Theaqueous layer was acidified to pH˜3 by adding 4% KHSO₄ dropwise. Thesolution was extracted with ethyl acetate (3×). Combined ethyl acetatelayers were washed with brine, dried (Na₂SO₄), filtered and concentratedunder reduced pressure to provide the titled compound. MS (CI) m/z 216(M+1)⁺.

Example 8C (5R)-1-(chloroacetyl)-5-ethynyl-L-prolinamide

To a stirred solution of (5R)-1-(chloroacetyl)-5-ethynyl-L-proline (1.89g, 8.76 mmol) in THF (50 mL) at −15° C. under nitrogen was added4-methylmorpholine (1.16 mL, 10.52 mmol), and then isobutylchloroformate(1.25 mL, 9.64 mmol) over 3 minutes. A white precipitate formed. Thereaction mixture was stirred at −15° C. under nitrogen for 30 minutes,and a solution of NH₃ in dioxane (0.5 M, 88 mL, 43.8 mmol) was added.The reaction mixture was stirred at −15° C. for 30 minutes, warmed toroom temperature, and stirred at that temperature for 16 hours. Thereaction mixture was diluted with 4% KHSO₄ to ˜pH 4 and extracted withethyl acetate (3×). The extracts were combined, washed with brine, dried(Na₂SO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography (60-75% ethyl acetate/hexane) providedthe titled compound. MS (CI) m/z 215 (M+1)⁺.

Example 8D (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of (5R)-1-(chloroacetyl)-5-ethynyl-L-prolinamide(0.16 g, 0.745 mmol) and imidazole (0.05 g, 0.745 mmol) in dry pyridine(4 mL) at −35° C. under nitrogen was added POCl₃ (0.15 mL, 1.49 mmol)dropwise. The reaction mixture was stirred between −35° C. to −15° C.for 1 hour and evaporated. The residue was diluted with dichloromethaneand washed with H₂O (2×), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. Purification by flash chromatography (10% ethylacetate/hexane) provided the titled compound. MS (CI) m/z 197 (M+1)⁺.

Example 8(2S,5R)-1-{N-((1R,2R,4S)-bicyclo(2.2.1)hept-2-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.152 mmol) in acetonitrile (1 mL) at room temperature was addedexo-2-aminonorborane (0.036 mL, 0.305 mmol) and a catalytic amount oftetrabutylammonium iodide. The reaction mixture was stirred at roomtemperature for 18 hours, concentrated under reduced pressure andpurified by flash chromatography with 3% methanol:dichloromethane toprovide the titled compound. MS (CI) m/z 271 (M+1)⁺; ¹H NMR (300 MHz,MeOH-d₄): δ ppm 4.7-4.8 (m, 2H), 3.61-3.8 (m, 2H), 3.2-3.3 (m, 1H),3.02-3.11 (1H, s), 2.62-2.72 (m, 1H), 2.37-2.44 (m, 3H), 2.2-2.3 (br s,2H), 1.0-1.7 (m, 8H).

Example 28 (2S,5S)-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile

The title compound was prepared in the manner described for example 6except methyl magnesium bromide was substituted for ethyl magnesiumbromide in the step corresponding to Example 6A. ¹H NMR (400 MHz,MeOH-d₄) δ 4.79 (dd, 1H, J=8.1 Hz), 4.40 (m, 1H), 4.30 (dd, 1H, J=4.1,9.4 Hz), 2.37-2.50 (m, 2H), 2.08 (m, 1H), 1.75-1.92 (m, 3H), 1.66 (m,1H), 1.36 (d, 3H, J=6.5 Hz), 1.05 (d, 3H, J=4.3 Hz), 1.04 (d, 3H, J=4.3Hz); ¹³C NMR (100 MHz, MeOH-d₄) δ 119.9 for CN group; MS (ESI) m/z 224(M+H)⁺.

Example 29(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrileExample 29A 4-Methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-ylamine

A stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzylester (0.15 g, 0.61 mmol, Example 30B) and 2-fluoropyridine (0.3 mL, 3.5mmol) was heated to 175° C. under microwave conditions for 1 hour. Thereaction mixture was concentrated under reduced pressure and purified bychromatography (silica gel, eluting with 20% to 35% ethyl acetate inhexane) to provide(4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acidbenzyl ester. MS (CI) m/z 326 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 8.06(dd 1H), 7.52 (m, 1H), 7.37-7.26 (m, 5H), 6.80 (d, 1H), 6.62 (t, 1H),5.04 (s, 2H), 4.84 (s, 1H), 3.78 (m, 2H), 3.25-3.16 (m, 2H), 2.08 (m,2H), 1.64-1.55 (m, 2H), 1.35 (s, 3H).

To a stirred solution of(4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acidbenzyl ester (0.06 g, 0.185 mmol) in isopropanol (1.8 mL) at roomtemperature was added ammonium formate (0.047 g, 0.75 mmol) and 5 mg of10% Pd/C under nitrogen. The reaction mixture was heated under microwaveconditions at 150° C. for 30 minutes, cooled, filtered through Celiteand concentrated under reduced pressure to provide the titled compound.MS (CI) m/z 192 (M+1).

Example 29B(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.039 g,0.2 mmol, Example 8D) in acetonitrile (3 mL) at room temperature wasadded 4-methyl-3,4,5,6-tetrahydro-2H-(1,3′)bipyridinyl-4-ylamine (0.076g, 0.4 mmol). The reaction mixture was stirred at 66° C. for 48 hours,concentrated under reduced pressure and purified by chromatography(silica gel, eluting with 2%-5% methanol:dichloromethane). The productwas mixed with 4M HCl in dioxane (2 mL), and after 0.5 hours, thesolvents were removed under reduced pressure. The residue was solidifiedby trituration with diethyl ether to provide the titled compound as theHCl salt. MS (CI) m/z 352 (M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δ ppm8.10 (m, 1H), 8.01 (d, 1H), 7.46 (d, 1H), 7.07 (t, 1H), 4.93 (m, 1H),4.77 (m, 1H), 4.39-4.15 (m, 3H), 3.59-3.46 (m, 4H), 3.24 (m, 1H),2.47-2.23 (m, 4H), 2.13-2.10 (m, 4H), 1.61 (m, 3H).

Example 30(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(3-cyano-pyridin-2-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrileExample 30A 4-Benzyloxycarbonylamino-4-methyl-piperidine-1-carboxylicacid tert-butyl ester

To a solution of the 4-methyl-piperidine-1,4-dicarboxylic acidmono-tert-butyl ester (5 g, 20.6 mmol) in toluene (40 mL) at 23° C. wasadded triethylamine (4.3 mL, 31 mmol) and diphenylphosphoryl azide (6.1mL, 28.0 mmol). The resulting mixture was stirred at 23° C. for 45minutes after which benzyl alcohol (11.1 mL, 103 mmol) was added. Thereaction mixture was then heated to 80° C. for 16 hours. The reactionmixture was allowed to cool to room temperature and the excess solventswere removed under reduced pressure. The crude residue was purified bychromatography (silica gel, eluting with 10% ethyl acetate/90% hexane to30% ethyl acetate/70% hexane) to provide the titled compound (5.6grams). MS (CI) m/z 249 (M-99)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 7.38-7.31(m, 5H), 5.05 (s, 2H), 4.57 (s, 1H), 3.67-3.60 (m, 2H), 3.18 (m, 2H),1.98-1.90 (m, 2H), 1.44 (s, 9H), 1.37 (s, 3H).

Example 30B (4-Methyl-piperidin-4-yl)-carbamic acid benzyl ester

A mixture of Example 30A (4.7 g, 13.4 mmol) in 4 M HCl in dioxane (20mL) was stirred at 23° C. for 12 hours. The dioxane was removed underreduced pressure and the crude solid was triturated several times withdiethyl ether. The resulting white solid was dried in vacuum ovenovernight to afford the HCl salt of the titled compound (2.75 g). MS(CI) m/z 249 (M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δ ppm 7.37-7.29 (m,5H), 5.05 (s, 2H), 3.19-3.07 (m, 4H), 1.76-1.70 (m, 4H), 1.37 (s, 3H).

Example 30C(5′-Cyano-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamicacid benzyl ester

A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl esterhydrochloride salt (198 mg, 0.697 mmol), 2-chloro-5-cyanopyridine (90mg, 0.65 mmol) and diisopropylethylamine (400 μL) in dioxane (2 mL) in asealed tube was heated to 170° C. under microwave conditions for 20minutes. The reaction mixture was cooled, concentrated and then purifiedby chromatography (silica gel, eluting with 10% hexane/ethyl acetate to60% ethyl acetate/hexane) to provide the titled compound (167 mg) as awhite foam. MS (CI) m/z 380 (M+1)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.45(s, 1H), 7.80 (dd, 1H), 7.37 (m, 5H), 7.18 (s, 1H), 6.93 (d, 1H), 5.00(s, 2H), 4.00-3.95 (m, 2H), 3.35-3.26 (m, 2H), 2.19-2.07 (m, 2H),1.49-1.43 (m, 2H), 1.27 (s, 3H).

Example 30D4-Amino-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carbonitrile

A solution of(5′-cyano-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamicacid benzyl ester (93 mg) and trimethylsilyliodide (62 μL) inacetonitrile (1.5 mL) was heated to 45° C. for 20 minutes. The reactionmixture was cooled and concentrated under reduced pressure. The crudereaction mixture was purified by chromatography (silica gel, elutingwith a gradient of 2% MeOH/CH₂Cl₂/0.1% NH₄OH to 6% MeOH/CH₂Cl₂/0.1%NH₄OH) to provide the titled compound (43 mg) as a yellow foam. MS (CI)m/z 217 (M+1)⁺; ¹H NMR (300 MHz, DMSO) δ ppm 8.44 (s, 1H), 7.77 (d, 1H),6.91 (d, 1H), 3.86-3.78 (m, 2H), 3.59-3.55 (m, 2H), 1.48-1.38 (m, 4H),1.08 (s, 3H).

Example 30(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(3-cyano-pyridin-2-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile

A mixture of Example 30D (60 mg, 0.31 mmol) and(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (105 mg,0.49 mmol, Example 8D) in acetonitrile (2 mL) was stirred at 23° C. for72 hours. The reaction mixture was concentrated under reduced pressure,and the crude residue was purified by chromatography (silica gel,eluting with 96% dichloromethane/4% methanol/0.1% ammonium hydroxide) toprovide the titled compound as a white foam. MS (CI) m/z 377 (M+1)⁺; ¹HNMR (300 MHz, CDCl₃) δ ppm 8.38 (s, 1H), 7.58 (dd, 1H), 6.59 (d, 1H),4.74 (t, 1H), 4.63-4.57 (m, 1H), 3.78-3.68 (m, 6H), 2.53 (s, 1H),2.43-2.34 (m, 2H), 1.69-1.50 (m, 4H), 1.19 (s, 3H).

Example 31(2S,5R)-5-ethynyl-1-(N-(1-(3-cyano-pyridin-3-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrileExample 31A4-Amino-3,4,5,6-tetrahydro-2H-(1,3′)bipyridinyl-5′-carbonitrile

Pd₂(dba)₃ (0.040 g, 0.044 mmol, XANTHPOS (0.070 g, 0.122 mmol), dioxane(5 mL), and Cs₂CO₃ (1.10 g, 3.15 mmol) were added into a dry Schlenkflask which was purged with nitrogen several times at room temperature.Then piperidin-4-yl-carbamic acid tert-butyl ester (0.50 g, 2.34 mmol)was added followed by 5-bromo-nicotinonitrile (0.52 g, 0.285 mmol) andpurging again with nitrogen. The reaction mixture was heated at 100° C.for 48 hours. The reaction was then cooled to room temperature and takenup in ethyl acetate (20 mL), washed with brine (2×) and water (2×),dried over MgSO₄, and concentrated under reduced pressure to provide thecrude product. The residue was purified by flash chromatography onsilica gel eluting with 5% to 35% ethylacetate in hexane. MS (CI) m/z303 (M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δ ppm 8.47 (d, 1H), 8.19 (m,1H), 7.65 (d, 1H), 4.84 (m, 1H), 3.83 (m, 2H), 3.60 (m, 1H), 3.01 (t,2H), 1.98 (m, 2H), 1.65-1.51 (m, 2H), 1.44 (s, 9H).

To a stirred solution of(5′-cyano-3,4,5,6-tetrahydro-2H-(1,3′)bipyridinyl-4-yl)-carbamic acidtert-butyl ester (0.45 g, 1.49 mmol) in dioxane (3.0 mL) at roomtemperature was added 4M HCl in dioxane (8 mL). The reaction mixture wasstirred at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, and the residue was treated withether. The solid obtained by filtration provided the titled compound. MS(CI) m/z 203 (M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δ ppm 8.68 (d, 1H),8.52 (s, 1H), 8.35 (m, 1H), 4.15-4.10 (m, 2H), 3.51-3.40 (m, 1H), 3.12(t, 2H), 2.20-2.15 (m, 2H), 1.82-1.69 (m, 2H).

Example 31B(2S,5R)-5-ethynyl-1-(N-(1-(3-cyano-pyridin-3-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.050 g,0.26 mmol, Example 8D) in acetonitrile (1.5 mL), dioxane (0.1.5 mL),dimethylformamide (0.5 mL), and water (0.5 mL) at room temperature wasadded 4-amino-3,4,5,6-tetrahydro-2H-(1,3′)bipyridinyl-5′-carbonitrilehydrochloride salt (0.028 g, 0.125 mmol) and diisopropylethylamine(0.145 mL, 0.41 mmol). The reaction mixture was stirred at roomtemperature for 48 hours, concentrated under reduced pressure andpurified by flash chromatography on silica eluting with 5% methanol indichloromethane. The product was mixed with 4M HCl in dioxane (4 mL) andafter 0.5 hour, the solvents were removed under reduced pressure, andthe residue was solidified by trituration with diethyl ether to providethe titled compound as the HCl salt. MS (CI) m/z 363 (M+1)⁺; ¹H NMR (300MHz, methanol-d₄) δ ppm 8.48 (d, 1H), 8.19 (d, 1H), 7.66 (m, 1H),4.81-4.72 (m, 1H), 3.88-3.86 (m, 2H), 3.80-3.60 (q, 2H), 3.09 (d, 1H),2.97-2.88 (m, 2H), 2.80-2.71 (m, 2H), 2.46-2.26 (m, 5H), 2.04 (m, 2H),1.54-1.44 (m, 2H).

Example 32(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-methoxycarbonylbenzoyl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrileExample 32A4-(4-Benzyloxycarbonylamino-4-methyl-piperidine-1-carbonyl)benzoic acidmethyl ester

To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzylester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) indichloromethane (3 mL) at room temperature was added methyl4-chlorocarbonylbenzoate (0.125 g, 0.62 mmol) and triethylamine (0.17mL, 1.2 mmol). The reaction mixture was stirred at room temperature for3 hours, aqueous ammonium chloride was added, and the mixture wasextracted with dichloromethane (2×). The combined organic layers werewashed with 10% KHSO₄, sat. NaHCO₃, brine, dried (MgSO₄), andconcentrated under reduced pressure to provide the titled compound. MS(CI) m/z 411 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 8.07 (d, 2H), 7.46(d, 2H), 7.33 (m, 5H), 5.06 (s, 2H), 4.63 (m, 1H—NH), 4.18-4.13 (m, 2H),3.95 (s, 3H), 3.36 (m, 2H), 2.09 (m, 2H), 1.78-1.42 (m, 2H), 1.41 (s,3H).

Example 32B 4-(4-Amino-4-methyl-piperidine-1-carbonyl)-benzoic acidmethyl ester

To a stirred solution of Example 32A (0.2 g, 0.49 mmol) in acetonitrile(4.0 mL) at room temperature was added iodotrimethysilane (0.11 mL, 0.75mmol). The reaction mixture was stirred at 50° C. for 30 minutes andthen concentrated under reduced pressure. The solid residue was washedwith acetone and ether and filtered to provide titled compound. MS (CI)m/z 277 (M+1)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.04 (d, 2H), 7.90 (bs,2H NH₂-DMSO solvent), 7.50 (d, 2H), 3.88 (s, 3H), 3.35-3.20 (m, 4H),1.79-1.58 (m, 4H), 1.35 (s, 3H).

Example 32(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-methoxycarbonylbenzoyl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.152 mmol, Example 8D) in acetonitrile (3 mL) at room temperature wasadded Example 32B (0.125 g, 0.31 mmol) and diisopropylethylamine (0.06mL, 0.31 mmol). The reaction mixture was stirred at room temperature for48 hours, concentrated under reduced pressure and purified by highpressure liquid chromatography with acetonitrile and water buffered withammonium acetate to provide the titled compound. MS (CI) m/z 437 (M+1)⁺;¹H NMR (300 MHz, CDCl₃) δ ppm 8.07 (d, 2H), 7.45 (d, 2H), 4.75 (m, 1H),4.59 (m, 1H), 3.94 (s, 3H), 3.17-3.91 (m, 6H), 2.55 (bs, 1H), 2.32-2.46(m, 5H), 1.40-1.82 (m, 4H), 1.19 (m, 3H).

Example 33(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile

Example 33 was prepared in the same manner as Example 40 by substituting2-fluoroisonicotinic acid for 6-fluoronicotinic acid. MS (CI) m/z 396(M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δ ppm 8.17 (d, 1H), 7.67 (s, 1H),7.31 (d, d 1H), 4.84 (m, 2H), 4.34-4.15 (m, 4H), 3.41-3.35 (m, 2H), 3.20(m, 1H), 2.52-2.24 (m, 5H), 2.07-2.00 (m, 4H), 1.59 (s, 3H).

Example 34(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrileExample 34A4-Methyl-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-ylamine

To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzylester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dioxane(1.0 mL) at room temperature was added2-chloro-5-trifluoromethyl-pyridine (0.11 g, 0.6 mmol) anddiisopropylethyl amine (0.21 mL, 1.2 mmol). The reaction mixture wasstirred at 150° C. in a microwave for 180 minutes, concentrated underreduced pressure and purified by flash chromatography with 30% ethylacetate in hexane to provide(4-methyl-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamicacid benzyl ester. MS (CI) m/z 394 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm8.38 (d, 1H), 7.61 (d, d 1H), 7.40-7.30 (m, 5H), 6.66 (d, 1H), 5.07 (s,2H), 4.71-4.67 (m, 1H), 3.93 (m, 2H), 3.36 (m, 2H), 2.10 (m, 2H), 1.68(m, 2H), 1.42 (s, 3H).

To a stirred solution of(4-methyl-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamicacid benzyl ester (0.37 g, 0.95 mmol) in acetonitrile (4.0 mL) at roomtemperature was added iodotrimethysilane (0.2 mL, 0.125 mmol). Thereaction mixture was stirred at 50° C. for 30 minutes, concentratedunder reduced pressure and purified by flash chromatography with 2%methanol in dichloromethane to provide the titled compound. MS (CI) m/z260 (M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δ ppm 8.31 (d, 1H), 7.67 (d, d1H), 6.87 (d, 1H), 4.83 (m, 2H), 3.79 (m, 2H), 3.63 (m, 2H), 1.63-1.54(m, 4H), 1.22 (s, 3H).

Example 34(2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.064 g,0.325 mmol, Example 8D) in acetonitrile (3 mL) at room temperature wasadded4-methyl-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-ylamine(0.110 g, 0.31 mmol) and diisopropylethylamine (0.15 mL, 0.86 mmol). Thereaction mixture was stirred at room temperature for 48 hours,concentrated under reduced pressure and purified by flash chromatographywith 1.5% methanol:dichloromethane. The product was mixed with 4M HCl indioxane (2 mL) and after 0.5 h, the solvent were removed under reducedpressure, and the residue was solidified by trituration with diethylether to provide the titled compound as the HCl salt. MS (CI) m/z 420(M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 8.38 (d, 1H), 7.60 (dd 1H), 6.63(d, 1H), 4.74 (m, 1H), 4.61 (m, 1H), 3.74-3.61 (m, 5H), 3.45 (m, 1H),2.51 (bs, 1H), 2.31-2.51 (m, 4H), 1.55-1.71 (m, 4H), 1.18 (m, 3H).

Example 35(2S,5R)-1-{N-(1-(4-chlorobenzoyl)piperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrileExample 35A (1-(4-Chloro-benzoyl)-piperidin-4-yl)-carbamic acidtert-butyl ester

To a stirred solution of piperidin-4-yl-carbamic acid tert-butyl ester(1 g, 5 mmol) and triethylamine (1.05 ml, 7.5 mmol) in THF (30 mL) at 0°C. was slowly added 4-chloro-benzoyl chloride (0.77 ml, 6 mmol). Thereaction mixture was stirred from 0° C. to room temperature for 2 hours.The reaction mixture was diluted with CH₂Cl₂ and washed with water (3times) and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated under reduced pressure to provide the titledcompound. MS (DCI) m/z 339 (M+H)⁺.

Example 35B (4-Amino-piperidin-1-yl)-(4-chloro-phenyl)-methanone

To a stirred solution of (1-(4-chloro-benzoyl)-piperidin-4-yl)-carbamicacid tert-butyl ester (46 g, 0.23 mmol) in CH₂Cl₂ (0.5 mL) was addedtrifluoroacetic acid (0.5 ml). The reaction mixture was stirred at roomtemperature for ½ hour. The reaction mixture was concentrated underreduced pressure to provide the titled compound. MS (DCI) m/z 239(M+H)⁺.

Example 35C(2S,5R)-1-{N-(1-(4-chlorobenzoyl)piperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.023 g,0.118 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded (4-amino-piperidin-1-yl)-(4-chloro-phenyl)methanone (56 mg, 0.235mmol). The reaction mixture was stirred at room temperature for 18hours, concentrated under reduced pressure and purified by flashchromatography with 3% methanol:dichloromethane to provide the titledcompound. MS (ESI) m/z 399 (M+H)⁺.

Example 36(2S,5R)-1-{N-(1-(5-chloropyridin-2-yl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrileExample 36A5′-Chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-ylamine

To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzylester (0.5 g, 2.02 mmol, Example 30B) in dioxane (5.0 mL) at roomtemperature was added 2,5-dichloro-pyridine (0.4 g, 2.79 mmol) anddiisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture wasstirred at 80° C. for 48 hours, concentrated under reduced pressure andpurified by flash chromatography with 10% to 40% ethyl acetate in hexaneto provide(5′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamicacid benzyl ester. MS (CI) m/z 360 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm8.01 (d, 1H), 7.49 (dd, 1H), 7.36-7.27 (m, 5H), 7.26 (m, 1H), 6.78 (d,1H), 5.04 (s, 2H), 3.82 (m, 2H), 3.21 (m, 2H), 2.15 (m, 2H), 1.58 (m,2H), 1.35 (s, 3H).

To a stirred solution of(5′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamicacid benzyl ester (0.060 g, 0.17 mmol) in acetonitrile (1.0 mL) at roomtemperature was added iodotrimethysilane (0.04 mL, 0.25 mmol). Thereaction mixture was stirred at 50° C. for 30 minutes, concentratedunder reduced pressure, and purified by flash chromatography with 3%methanol in dichloromethane to provide titled compound. MS (CI) m/z 226(M+1)⁺.

Example 36(2S,5R)-1-{N-(1-(5-chloropyridin-2-yl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.013 g,0.066 mmol, Example 8D) in acetonitrile (0.75 mL) and dioxane (0.75 mL)at room temperature was added5′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-ylamine(0.028 g, 0.125 mmol). The reaction mixture was stirred at 70° C. for 48hours, concentrated under reduced pressure and purified by high pressureliquid chromatography with acetonitrile and water containing 0.02% TEA.The residue was solidified by trituration with diethyl ether to providethe titled compound as the TFA salt. MS (CT) m/z 386 (M+1)⁺; ¹H NMR (300MHz, methanol-d₄) δ ppm 8.10 (m, 1H), 7.56 (d, d, 1H), 6.87 (d, 1H),4.93 (m, 1H), 4.81 (m, 2H), 4.34-4.12 (m, 4H), 3.35 (m, 1H), 3.23 (d,1H), 3.15-3.06 (m, 2H), 2.46-2.31 (m, 4H), 1.88-1.99 (m, 4H), 1.55 (m,3H).

Example 37(2S,5R)-5-ethynyl-1-(N-(1-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrileExample 37A 3,4,5,6-Tetrahydro-2H-(1,2′)bipyridinyl-4-ylamine

Pd₂(dba)₃ (0.040 g, 0.044 mmol), XANTHPOS (0.070 g, 0.122 mmol), dioxane(5 mL), and Cs₂CO₃ (1.10 g, 3.15 mmol) were added into a dry Schlenkflask which was purged with nitrogen several times at room temperature.Then piperidin-4-yl-carbamic acid tert-butyl ester (0.50 g, 2.34 mmol)was added followed by 2-bromopyridine (0.452 g, 0.285 mmol) andadditional nitrogen purges. The reaction mixture was heated at 100° C.for 48 hours. The reaction was then cooled to room temperature, taken upin ethyl acetate (20 mL), washed with brine (2×), water (2×), dried overMgSO₄, and concentrated under reduced pressure. The residue was purifiedby flash chromatography with 5% to 35% ethyl acetate in hexane. MS (CI)m/z 278 (M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δ ppm 8.03 (d, 1H), 7.57(t, 1H), 6.86 (d, 1H), 6.65 (t, 1H), 4.84 (m, 1H), 4.16 (m, 2H), 3.58(m, 1H), 3.04-2.95 (m, 2H), 1.92 (m, 2H), 1.52-1.47 (m, 2H), 1.44 (s,9H).

To a stirred solution of(3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid tert-butylester (0.45 g, 1.49 mmol) in dioxane (3.0 mL) at room temperature wasadded 4M HCl in dioxane (8 mL). The reaction mixture was stirred at roomtemperature 30 minutes. The reaction mixture was concentrated underreduced pressure, and the residue treated with ether. The titledcompound was collected by filtration. MS (CI) m/z 203 (M+1)⁺.

Example 37(2S,5R)-5-ethynyl-1-(N-(1-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.027 g,0.14 mmol. Example 8D) in acetonitrile (0.5 mL), dioxane (0.5 mL), andwater (0.7 mL) at room temperature was added3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-ylamine (0.028 g, 0.125 mmol)and diisopropylethylamine (0.072 mL, 0.41 mmol). The reaction mixturewas stirred at room temperature for 48 hours, concentrated under reducedpressure and purified by flash chromatography with 5% methanol indichloromethane. The product was mixed with 4M HCl in dioxane (2 mL),and after 0.5 h, the volatiles were removed under reduced pressure, andthe residue was solidified by trituration with diethyl ether to providethe titled compound as the HCl salt. MS (CI) m/z 338 (M+1)⁺; ¹H NMR (300MHz, methanol-d₄) δ ppm 8.09 (m, 1H), 7.99 (d, 1H), 7.47 (d, 1H), 7.05(t, 1H), 4.88 (m, 1H), 4.45-4.19 (m, 5H), 3.61-3.35 (m, 2H), 3.21 (m,1H), 2.47-2.33 (m, 6H), 1.86-1.82 (m, 2H), 1.37-1.15 (m, 2H).

Example 38(2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrileExample 38A4-Methyl-1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-ylamine

To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzylester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dioxane(1.0 mL) at room temperature was added2-chloro-4-trifluoromethyl-pyrimidine (0.1 g, 0.55 mmol) anddiisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture wasstirred at 150° C. in a microwave for 30 minutes, concentrated underreduced pressure and purified by flash chromatography with 30% ethylacetate and hexane to provide(4-methyl-1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl)-carbamicacid benzyl ester. MS (CI) m/z 395 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm8.48 (d, 1H), 7.37-7.32 (m, 5H), 6.72 (d, 1H), 5.08 (s, 2H), 4.67 (bs,1H), 4.22 (m, 2H), 3.49 (m, 2H), 2.08 (m, 2H), 1.68-1.60 (m, 2H), 1.35(s, 3H).

To a stirred solution of(4-methyl-1-(4-trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yl)-carbamicacid benzyl ester (0.060 g, 0.17 mmol) in acetonitrile (1.0 mL) at roomtemperature was added iodotrimethysilane (0.04 mL, 0.25 mmol). Thereaction mixture was stirred at 50° C. for 30 minutes, concentratedunder reduced pressure and purified by flash chromatography with 3%methanol in dichloromethane to provide the titled compound. MS (CI) m/z261 (M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δ ppm 8.61 (d, 1H), 6.92 (d,1H), 4.83 (m, 2H), 4.50 (m, 2H), 3.51 (m, 2H), 1.90-1.74 (m, 4H), 1.51(s, 3H).

Example 38(2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g,0.205 mmol, Example 8D) in acetonitrile (3 mL) at room temperature wasadded Example 38A (0.140 g, 0.54 mmol) and diisopropylethylamine (0.10mL, 0.58 mmol). The reaction mixture was stirred at room temperature for48 hours, concentrated under reduced pressure and purified by flashchromatography with 3% methanol:dichloromethane with 0.03% ammonia. Theproduct was mixed with 4M HCl in dioxane (2 mL), and after 0.5 h, thesolvent were removed under reduced pressure and the residue wassolidified by trituration with diethyl ether to provide the titledcompound as the HCl salt. MS (CI) m/z 421 (M+1)⁺; ¹H NMR (300 MHz,methanol-d₄) δ ppm 8.61 (d, 1H), 6.95 (d, 1H), 4.85 (m, 2H), 4.21 (q,2H), 3.12-3.23 (m, 6H), 2.28-2.45 (m, 4H), 1.80-2.03 (m, 4H), 1.6 (m,3H).

Example 39(2S,5R)-5-ethynyl-1-(N-(1-isonicotinoyl-4-methylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrileExample 39A (4-Amino-4-methyl-piperidin-1-yl)-pyridin-4-yl-methanone

To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzylester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) indichloromethane (3 mL) at room temperature was added isonicotinoylchloride (0.4 g, 2.79 mmol) and triethylamine (0.17 mL, 1.2 mmol). Thereaction mixture was stirred at room temperature for 3 hours, aqueousammonium chloride was added, and the mixture was extracted withdichloromethane (2×). Combined organic layers were washed with 10%KHSO₄, sat. NaHCO₃, and brine before drying (MgSO₄), and concentrationunder reduced pressure to provide(4-methyl-1-(pyridine-4-carbonyl)-piperidin-4-yl)-carbamic acid benzylester. MS (CI) m/z 354 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 8.69 (d,2H), 7.40-7.31 (m, 7H), 5.06 (s, 2H), 4.15 (m, 1H), 4.62 (m, 4H), 2.12(m, 2H), 1.77-1.45 (m, 2H), 1.42 (s, 3H).

To a stirred solution(4-methyl-1-(pyridine-4-carbonyl)-piperidin-4-yl)-carbamic acid benzylester (0.085 g, 0.24 mmol) in acetonitrile (2.0 mL) at room temperaturewas added iodotrimethysilane (0.06 mL, 0.36 mmol). The reaction mixturewas stirred at 50° C. for 30 minutes and concentrated under reducedpressure. The solid residue was washed with acetone and filtered toprovide titled compound. MS (CI) m/z 220 (M+1)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.89 (d, 2H), 7.74 (d, 2H), 4.04 (m, 2H, NH2), 3.42-3.25(m, 4H), 1.77-1.45 (m, 4H), 1.42 (s, 3H).

Example 39(2S,5R)-5-ethynyl-1-(N-(1-isonicotinoyl-4-methylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.152 mmol, Example 8D) in acetonitrile (3 mL) at room temperature wasadded (4-amino-4-methyl-piperidin-1-yl)-pyridin-4-yl-methanone (0.110 g,0.31 mmol) and diisopropyl ethyl amine (0.06 mL, 0.31 mmol). Thereaction mixture was stirred at room temperature for 48 hours,concentrated under reduced pressure and purified by high pressure liquidchromatography with acetonitrile and water buffered with ammoniumacetate. The product was mixed with 4M HCl in dioxane (2 mL) and after0.5 hours, the solvent were removed under reduced pressure, and theresidue was solidified by trituration with ether to provide the titledcompound as the HCl salt. MS (CI) m/z 380 (M+1)⁺; ¹H NMR (300 MHz,CDCl₃) δ ppm 8.69 (d, 2H), 7.27 (d, 2H), 4.78 (m, 1H), 4.59 (m, 1H),4.01 (m, 1H), 3.2-3.75 (m, 6H), 2.62 (bs, 1H), 2.31-2.58 (m, 4H),1.41-1.78 (m, 4H), 1.17 (m, 3H).

Example 40(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(5-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrileExample 40A 6-Fluoro-nicotinic acid tert-butyl ester

To a stirred and refluxed solution of 6-fluoro-nicotinic acid (0.092 g,6.52 mmol) in benzene and 2-methyl-propan-2-ol (2:1, 15:7 mL) was addeddropwise N,N-dimethylformamide di-tert-butyl acetal (8.2 mL, 29.6 mmol).The reaction mixture was refluxed for 3 hours, cooled to roomtemperature and partitioned between aqueous NaHCO₃ and dichloromethane.The organic layer was washed with water and brine, dried (MgSO₄),filtered, concentrated under reduced pressure and purified by flashchromatography with 15% to 30% ethyl acetate in hexane to provide thetitled compound. MS (CI) m/z 197 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm8.82 (d, 1H), 8.38 (m, 1H), 6.98 (d, 1H), 1.64 (s, 9H).

Example 40B4-Amino-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carboxylicacid tert-butyl ester

To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzylester (0.31 g, 1.28 mmol, Example 30B) in dioxane (5.0 mL) at roomtemperature was added 6-fluoro-nicotinic acid tert-butyl ester (0.21 g,1.07 mmol). The reaction mixture was stirred at 80° C. for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 10% to 30% ethyl acetate in hexane to provide4-benzyloxycarbonylamino-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carboxylicacid tert-butyl ester. MS (CT) m/z 426 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δppm 8.74 (d, 1H), 7.97 (dd, 1H), 7.35 (m, 5H), 7.26 (s, 1H), 5.07 (s,2H), 4.68 (s, 1H), 3.97 (m, 2H), 3.37 (m, 2H), 2.08 (m, 2H), 1.66 (m,2H), 1.56 (s, 9H), 1.42 (s, 3H).

To a stirred solution of4-benzyloxycarbonylamino-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carboxylicacid tert-butyl ester (0.29 g, 0.68 mmol) in isopropanol, methanol andethyl acetate (1:1:1, 5.0 mL) at room temperature was added ammoniumformate (0.25 g, 1.07 mmol) and 10% Pd/C (25 mg) under nitrogen. Thereaction mixture was stirred at 80° C. for 30 minutes, cooled, filteredthrough Celite, and concentrated under reduced pressure to provide thetitled compound. MS (CT) m/z 292 (M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δppm 8.61 (d, 1H), 7.95 (d, d 1H), 6.79 (d, 1H), 4.80 (s, 2H), 3.85-3.79(m, 2H), 3.66-3.60 (m, 2H), 1.67-1.59 (m, 4H), 1.58 (s, 9H), 1.23 (s,3H).

Example 40(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(5-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.058 g,0.30 mmol, Example 8D) in dioxane (3.0 mL) and water (11.0 mL) at roomtemperature was added4-amino-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-5′-carboxylicacid tert-butyl ester (0.170 g, 0.58 mmol). The reaction mixture wasstirred at room temperature for 48 hours, concentrated under reducedpressure and purified by flash chromatography with 5% methanol indichloromethane. The product was mixed with TFA in dichloromethane (1:1,6 mL), and after 2 h, the volatiles were removed under reduced pressure.The residue was solidified by trituration with diethyl ether to providethe titled compound as the TFA salt. MS (CI) m/z 396 (M+1)⁺; ¹H NMR (300MHz, methanol-d₄) δ ppm 8.68 (d, 1H), 8.15 (d, d, 1H), 7.03 (d, 1H),4.84 (m, 2H), 4.47 (d, 2H), 4.32-4.14 (q, 2H), 3.31-3.25 (m, 2H), 3.20(d, 1H), 2.51-2.23 (m, 5H), 2.06-1.93 (m, 4H), 1.59 (m, 3H).

Example 41(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(5-cyano-pyridin-3-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrileExample 41A4-Amino-4-methyl-3,4,5,6-tetrahydro-2H-(1,3′)bipyridinyl-5′-carbonitrile

Pd(AcO)₂ (0.008 g, 0.036 mmol, BINAP (0.032 g, 0.052 mmol) toluene (3mL), and Cs₂CO₃ (0.280 g, 0.85 mmol) were added into a dry Schlenk flaskwhich was purged with nitrogen several times at room temperature. Then(4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.280 g, 0.85mmol. Example 30B) was added followed by 5-bromo-nicotinonitrile (0.280g, 0.85 mmol), and the reaction vessel was purged with nitrogen again.The reaction mixture was heated at 100° C. for 72 hours. The reactionwas then cooled to room temperature and taken up in ethyl acetate (20mL), washed with brine (2×), water (2×), dried over MgSO₄, andconcentrated under reduced pressure to give crude product. The residuewas purified by flash chromatography with 10% to 35% ethylacetate/hexane. MS (CI) m/z 351 (M+1)⁺.

To a stirred solution of(5′-cyano-4-methyl-3,4,5,6-tetrahydro-2H-(1,3′)bipyridinyl-4-yl)-carbamicacid benzyl ester (0.051 g, 0.15 mmol) in isopropanol, (3.0 mL) at roomtemperature was added ammonium formate (0.050 g, 0.8 mmol) and 10% Pd/C(15 mg) under nitrogen. The reaction mixture was stirred at 90° C. for18 hours, cooled, filtered through Celite and concentrated under reducedpressure to provide the titled compound. MS (CT) m/z 292 (M+1)⁺; ¹H NMR(300 MHz, methanol-d₄) δ ppm 8.48 (d, 1H), 8.18 (d, 1H), 7.65 (m, 1H),3.49-3.36 (m, 2H), 3.32-3.36 (m, 2H), 1.73-1.61 (m, 4H), 1.20 (s, 3H).

Example 41B(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(5-cyano-pyridin-3-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.013 g,0.066 mmol, Example 8D) in acetonitrile (0.8 mL) at room temperature wasadded4-amino-4-methyl-3,4,5,6-tetrahydro-2H-(1,3′)bipyridinyl-5′-carbonitrile(0.028 g, 0.13 mmol). The reaction mixture was stirred at 70° C. for 48hours, concentrated under reduced pressure and purified by flashchromatography with 2-4% methanol:dichloromethane. The product was mixedwith 4M HCl in dioxane (2 mL) and after 0.5 h, the volatiles wereremoved under reduced pressure, and the residue was solidified bytrituration with diethyl ether to provide the titled compound as the HClsalt. MS (CI) m/z 377 (M+1)⁺; ¹H NMR (300 MHz, methanol-d₄) δ ppm 8.48(d, 1H), 8.18 (d, 1H), 7.66 (m, 1H), 5.01 (m, 1H), 4.77-5.0 (m, 2H),3.78-3.45 (m, 4H), 3.34 (m, 1H), 3.08 (d, 1H), 2.51 (bs, 1H), 2.05-2.41(m, 4H), 1.70-1.77 (m, 4H), 1.19 (m, 3H).

Example 42(2S,5R)-5-ethynyl-1-(N-trans(4-hydroxycyclohexyl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.030 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded trans-4-aminocyclohexanol (35 mg, 0.31 mmol). The reaction mixturewas stirred at room temperature for 18 hours, concentrated under reducedpressure and purified by flash chromatography with 3%methanol:dichloromethane to provide the titled compound. MS (ESI) m/z276 (M+H)⁺; ¹H NMR (CDCl₃) δ 4.73 (m, 1H), 4.60 (m, 1H), 3.62 (m, 2H),3.60 (m, 1H), 2.52 (d, 1H), 2.48 (m, 1H), 2.38 (m, 2H), 1.98 (m, 4H),1.25 (m, 4H).

Example 43 (2S,5R)-5-ethynyl-1-(N-(4-trans{(4′-fluoro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrileExample 43A 4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) inDMF (3 mL) at 0° C. was added 60% NaH in mineral oil (120 mg, 3 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then3-bromo-4-fluoro-1-trifluoromethyl benzene (0.17 ml, 1.2 mmol) wasadded. It was heated to 60° C. for 2 hours and stirred for 12 hours atroom temperature. The reaction mixture was diluted with ethyl acetateand washed with water (3 times) and brine. The organic layer was dried(sodium sulfate), filtered, and concentrated under reduced pressure toprovide the titled compound. MS (DCI) m/z 338 (M+H)⁺.

Example 43B(4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexyl)-carbamic acidtert-butyl ester

To a cold solution (0° C.) of4-(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine (1 mmol) and NEt₃(0.42 ml, 3 mmol) in CH₂Cl₂ (5 mL) was added (Boc)₂O (261 mg, 1.2 mmol)in CH₂Cl₂ (1 mL) solution via syringe. The reaction mixture was stirredfrom 0° C. to room temperature for 2 hours. It was diluted with CH₂Cl₂and washed with water (2 times) and brine. The organic layer was dried(sodium sulfate), filtered, concentrated under reduced pressure andpurified by flash chromatography with 30% ethyl acetate/hexane toprovide the titled compound. MS (ESI) m/z 438 (M+H)⁺.

Example 43C(4-trans(4′-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-cyclohexyl)-carbamicacid tert-butyl ester

To a cold solution of(4-(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexyl)-carbamic acidtert-butyl ester (219 mg, 0.5 mmol) in isopropanol (5 mL) was added4-fluorophenylboronic acid (84 mg, 0.6 mmol), Pd(PPh₃)₂Cl₂ (35 mg, 0.05mmol), and K₂CO₃ (207 mg, 1.5 mmol). The reaction mixture was heated to85° C. for 3 hours. It was diluted with ethyl acetate and washed withwater (2 times) and brine. The organic layer was dried (sodium sulfate),filtered, concentrated under reduced pressure and purified by flashchromatography with 30% ethyl acetate/hexane to provide the titledcompound. MS (ESI) m/z 454 (M+H)⁺.

Example 43D4-trans(4′-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-cyclohexylamine

To a solution of(4-(4′-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-cyclohexyl)-carbamicacid tert-butyl ester (139 mg, 0.31 mmol) in CH₂Cl₂ (1 mL) was added 4NHCl/dioxane (3 ml). The reaction mixture was stirred at room temperaturefor 3 hours and concentrated under reduced pressure to provide thetitled compound. MS (ESI) m/z 354 (M+H)⁺.

Example 43(2S,5R)-5-ethynyl-1-(N-(4-trans{(4′-fluoro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(4′-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-cyclohexylamine(0.31 mmol) and NEt₃ (0.063 ml, 0.45 mmol). The reaction mixture wasstirred at room temperature for 18 hours, concentrated under reducedpressure and purified by flash chromatography with 3%methanol:dichloromethane to provide the titled compound. MS (ESI) m/z514 (M+H)⁺; ¹H NMR (DMSO) δ 7.58 (m, 3H), 7.43 (d, 1H), 7.25 (m, 2H),7.15 (d, 1H), 4.98 (m, 1H), 4.85 (m, 1H), 4.35 (m, 2H), 3.87 (m, 1H),3.14 (m, 1H), 2.29-2.45 (m, 3H); 2.15 (m, 6H), 1.60 (m, 4H).

Example 44(2S,5R)-5-ethynyl-1-(N-{4-trans(4-(trifluoromethoxy)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrileExample 44A 4-trans(trifluoromethoxy-phenoxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (230 mg, 2 mmol) inDMF (10 mL) at 0° C. was added 60% NaH in mineral oil (240 mg, 6 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then1-fluoro-4-(trifluoromethoxy)benzene (432 mg, 2.4 mmol) was added. Itwas heated to 60° C. for 2 hours and stirred for 12 hours at roomtemperature. The reaction mixture was diluted with ethyl acetate andwashed with water (3 times) and brine. The organic layer was dried(sodium sulfate), filtered, and concentrated under reduced pressure toprovide the titled compound. MS (DCI) m/z 276 (M+H)⁺.

Example 44(2S,5R)-5-ethynyl-1-(N-{4-trans(4-(trifluoromethoxy)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(trifluoromethoxy-phenoxy)-cyclohexylamine (84 mg, 0.31 mmol).The reaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 436 (M+H)⁺; ¹H NMR (CD₃OD) δ 7.19 (d, 2H), 6.99 (d, 2H), 4.32(m, 2H), 4.18 (m, 1H), 3.21 (m, 1H), 2.44 (d, 3H), 2.27 (m, 6H); 1.67(m, 2H); 1.55 (m, 2H), 1.37 (m, 2H).

Example 45(2S,5R)-5-ethynyl-1-(N-(4-hydroxy-1-methylcyclohexyl)glycyl)pyrrolidine-2-carbonitrileExample 45A 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanecarboxylicacid ethyl ester

To a solution of 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (10.32g, 59.92 mmol) in dimethylformamide (50 mL) was added imidazole (8.16 g,119.8 mmol), followed by tert-butyldimethylsilyl chloride (9.94 g, 65.9mmol). The resulting mixture was stirred at room temperature for 16hours. Diethyl ether was added (150 mL), and the mixture was washed with1M HCl (150 mL). The aqueous layer was extracted with diethyl ether (150mL). The combined organic layers were washed with 1M HCl (100 mL) andsaturated sodium chloride solution (100 mL), dried over magnesiumsulfate, filtered and concentrated to afford a clear oil. MS (CI) m/z287 (M+1)⁺

Example 45B 4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanecarboxylicacid

To a solution of Example 45A (6.6 g, 23.0 mmol) in tetrahydrofuran (31mL) and methanol (20 mL) was added lithium hydroxide monohydrate (1.93g, 46.1 mmol). The resulting mixture was heated at 60° C. for 2 hours.The heat was removed and the reaction mixture was stirred at roomtemperature overnight. The solvents were removed in vacuo and thesolution was neutralized with 1M HCl. Ethyl acetate (200 mL) was addedand the layers were separated. The aqueous layer was further extractedwith ethyl acetate (2×200 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated to give the titledcompound (4.5 g). MS (CI) m/z 259 (M+1)⁺

Example 45C4-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-cyclohexanecarboxylic acid

To a cold (−78° C.) of diisopropylamine (3.44 mL, 24.5 mmol) intetrahydrofuran (49 mL) was added n-butyl lithium (2.5 M in hexanes,9.81 mL, 24.5 mmol) dropwise over 10 minutes. The ice bath was removed,and the reaction mixture was allowed to warm to 0° C. and then cooledback to −78° C. A solution of Example 45B (3.3 g, 12.3 mmol) intetrahydrofuran (10 mL) was then added. The ice bath was removed and thereaction mixture was heated at 50° C. for 2 hours. The reaction mixturewas then cooled back to −78° C. and methyl iodide (0.84 mL, 13.5 mmol)was added followed by stirring for 2 hours. The cooling bath wasremoved, and the reaction mixture was stirred at room temperature for 1hour. The reaction solution was then poured into diethyl ether (200 mL)and 1M HCl (200 mL). The layers were separated and the aqueous layer wasfurther extracted with diethyl ether (2×200 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated to acrude yellow oil. The crude oil was purified by flash chromatographywith 15% ethyl acetate/84% hexane/1% methanol to afford the titledcompound (2.37 g) as a light yellow oil. MS (CI) m/z 273 (M+1)⁺.

Example 45D(4-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-cyclohexyl)-carbamic acidbenzyl ester

To a solution of example 45C (832 mg, 3.05 mmol) and triethylamine (596μL, 4.27 mmol) in toluene (15 mL) was added diphenylphosphoryl azide(791 μL, 3.66 mmol) via syringe. The resulting light amber solution wasstirred at 23° C. for 1 hour, then benzyl alcohol (1.6 mL, 15.25 mmol)was added. The solution was then heated at 75° C. for 24 hours. Thereaction mixture was cooled and the solvents removed in vacuo. The crudeoil was purified by flash chromatography using a linear gradient of 95%hexane/5% ethyl acetate to 30% ethyl acetate/70% hexane to give thetitle compound (995 mg) as an inseparable mixture of diastereomers. MS(CI) m/z 378 (M+1)⁺; ¹H NMR (300 MHz, DMSO) δ ppm 7.37-7.28 (m, 10H),6.86 (s, 1H), 6.82 (s, 1H), 4.96 (s, 2H), 4.95 (s, 2H), 3.80-3.70 (m,2H), 3.62-3.50 (m, 2H), 2.05 (d, 2H), 1.79-1.75 (m, 2H), 1.64-1.20 (m,8H), 1.19 (s, 3H), 1.16 (s, 3H), 0.84 (s, 9H), 0.83 (s, 9H), 0.02 (s,12H).

Example 45E (4-Hydroxy-1-methyl-cyclohexyl)-carbamic acid benzyl ester

To a solution of example 45D (341 mg, 0.91 mmol) in tetrahydrofuran (5mL) was added tetrabutylammonium fluoride (1 M solution in THF, 2.0 mL,2 mmol). The resulting brown solution was stirred at room temperaturefor 24 hours and then concentrated in vacuo and partitioned betweenethyl acetate (100 mL) and water (100 mL). The organic layer was driedover sodium sulfate, filtered and concentrated to afford a crude oil.The crude oil was purified by flash chromatography using a lineargradient of 80% hexane/20% ethyl acetate to 80% ethyl acetate/20% hexaneto give the title compound (185 mg) as an inseparable mixture ofdiastereomers. MS (CI) m/z 264 (M+1)⁺.

Example 45F 4-Amino-4-methyl-cyclohexanol

A mixture of example 45E (169 mg, 0.64 mmol), ammonium formate (105 mg,1.67 mmol) and 10% palladium on carbon (7 mg) in isopropanol (5 mL) washeated at 80° C. for 1 hour. The reaction mixture was cooled andfiltered through a plug of Celite. The filter pad was washed with ethylacetate (50 mL), and the filtrate was concentrated in vacuo to affordthe titled compound as an inseparable mixture of diastereomers. MS (CI)m/z 130 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 3.77-3.71 (m, 2H),3.65-3.61 (m, 2H), 1.87-1.61 (m, 4H), 1.63-1.33 (m, 10H), 1.15 (s, 3H),1.11 (s, 3H).

Example 45(2S,5R)-5-ethynyl-1-(N-(4-hydroxy-1-methylcyclohexyl)glycyl)pyrrolidine-2-carbonitrile

A mixture of example 45F (66 mg, 0.51 mmol) and example 8D (50 mg, 0.26mmol) in acetonitrile (1 mL) was stirred at 23° C. for 48 hours. Thereaction mixture was concentrated and the crude material was purified byflash chromatography using a step gradient of 3% methanol/97%dichloromethane to 5% methanol/95% dichloromethane to give the free baseof the title compound (33 mg) as an inseparable mixture ofdiastereomers. The HCl salt was prepared by taking the free base up indiethyl ether, adding the appropriate amount of 1M HCl in diethyl etherand removing the solvent in vacuo. MS (CI) m/z 290 (M+1)⁺; ¹H NMR (300MHz, MeOH-d₄) δ ppm 3.94-3.83 (m, 8H), 3.80-3.70 (m, 2H), 3.64-3.59 (m,2H), 3.16 (d, 1H), 3.15 (d, 1H), 2.50-2.28 (m, 8H), 1.95-1.45 (m, 14H),1.29 (s, 3H), 1.23 (s, 3H).

Example 46(2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(pyridin-3-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrileExample 46A 1-Methyl-4-trans(pyridin-3-yloxy)-cyclohexylamine

To a mixture of sodium hydride (46 mg, 2.0 mmol) in dimethylformamide (5mL) at 0° C. was added example 45F (116 mg, 0.9 mmol). The resultingmixture was stirred at 23° C. for 30 minutes, then 3-fluoropyridine (73μL, 0.85 mmol) was added. The mixture was then heated at 80° C. for 1hour and then cooled. The reaction mixture was poured into saturatedsodium bicarbonate solution (50 mL). The solution was then extractedwith ethyl acetate (3×50 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated. The crude material waspurified by flash chromatography using a step gradient of 2%methanol/97.9% dichloromethane/0.1% ammonium hydroxide to 6%methanol/93.9% dichloromethane/0.1%) ammonium hydroxide to give thetitle compound (119 mg). MS (CI) m/z 207 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃)δ ppm 8.31 (d, 1H), 8.19 (t, 1H), 7.19 (d, 2H), 4.41-4.36 (m, 1H),2.05-1.90 (m, 2H), 1.76-1.70 (m, 2H), 1.50-1.38 (m, 4H), 1.20 (s, 3H).

Example 46(2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(pyridin-3-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile

A mixture of example 46A (105 mg, 0.51 mmol) and example 8D (50 mg, 0.26mmol) in acetonitrile (0.75 mL) was stirred at 23° C. for 48 hours. Thereaction mixture was concentrated and the crude material was purified byflash chromatography using a linear gradient of 2% methanol/97.9%dichloromethane/0.1% ammonium hydroxide to 6% methanol/93.9%dichloromethane/0.1% ammonium hydroxide to give the title compound (43mg) as its free base. The HCl salt was prepared by taking the free baseup in diethyl ether, adding the appropriate amount of 1M HCl in diethylether and removing the solvent in vacuo. MS (CT) m/z 367 (M+1)⁺; ¹H NMR(300 MHz, MeOH-d₄) δ ppm 8.67 (d, 1H), 8.65 (d, 1H), 8.29 (dd, 1H), 8.02(dd, 1H), 4.93 (m, 1H), 4.80-4.72 (m, 1H), 4.25 (AB quartet, 2H), 3.24(d, 1H), 2.50-2.15 (m, 6H), 2.10-1.75 (m, 6H), 1.52 (s, 3H).

Example 47(2S,5R)-1-(N-{4-trans((5-chloropyridin-3-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrileExample 47A 4-trans(5-chloro-pyridin-3-yloxy)cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (230 mg, 2 mmol) inDMF (5 mL) at 0° C. was added 60% NaH in mineral oil (240 mg, 6 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then3-chloro-5-fluoro-pyridine (0.21 ml, 2.4 mmol) was added. It was heatedto 60° C. for 2 hours and stirred for 12 hours at room temperature. Thereaction mixture was diluted with ethyl acetate and washed with water (3times) and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated under reduced pressure to provide the titledcompound. MS (DCI) m/z 227 (M+H)⁺.

Example 47(2S,5R)-1-(N-{4-trans((5-chloropyridin-3-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(5-chloro-pyridin-3-yloxy)cyclohexylamine (70 mg, 0.31 mmol).The reaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 387 (M+H)⁺; ¹H NMR (CDCl₃) δ 8.17 (m, 2H), 7.19 (m, 1H), 4.74(m, 1H), 4.59 (m, 1H), 4.24 (m, 1H), 3.63 (m, 2H), 2.61 (m, 1H), 2.53(d, 1H), 2.40 (m, 4H), 2.15 (m, 2H), 2.04 (m, 2H), 1.54 (m, 2H), 1.33(m, 2H).

Example 48(2S,5R)-1-{N-(4-trans(4-cyanophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrileExample 48A 4-(4-transaminocyclohexyloxy)-benzonitrile

To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) inDMF (6 mL) at 0° C. was added 60% NaH in mineral oil (120 mg, 3 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then4-fluorobenzonitrile (151 mg, 1.25 mmol) was added. It was heated to 60°C. for 2 hours and stirred for 12 hours at room temperature. Thereaction mixture was diluted with ethyl acetate and washed with water (3times) and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated under reduced pressure to provide the titledcompound. MS (DCI) m/z 111 (M+H)⁺.

Example 48(2S,5R)-1-{N-(4-trans(4-cyanophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(4-aminocyclohexyloxy)-benzonitrile (66 mg, 0.31 mmol). Thereaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 377 (M+H)⁺; ¹H NMR (DMSO) δ 7.74 (d, 2H), 7.14 (d, 2H), 4.95(m, 1H), 4.84 (m, 1H), 4.39 (m, 1H), 3.92 (m, 1H), 3.44 (m, 2H), 3.16(m, 1H), 2.28 (m, 2H), 2.17 (m, 6H), 2.14 (d, 1H), 1.53 (m, 4H).

Example 49(2S,5R)-5-ethynyl-1-(N-(4-trans{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrileExample 49A 4-trans(5-trifluoromethyl-pyridin-2-yloxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (345 mg, 3 mmol) inDMF (10 mL) at 0° C. was added 60% NaH in mineral oil (360 mg, 6 mmol).The reaction mixture was stirred at 0° C. for ½ hour, and then2-chloro-5-(trifluoromethyl)pyridine (652 mg, 3.6 mmol) was added. Itwas heated to 60° C. for 2 hours and stirred for 12 hours at roomtemperature. The reaction mixture was diluted with ethyl acetate andwashed with water (3 times) and brine. The organic layer was dried(sodium sulfate), filtered, and concentrated under reduced pressure toprovide the titled compound. MS (DCI) m/z 261 (M+H)⁺.

Example 49(2S,5R)-5-ethynyl-1-(N-(4-trans{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(5-trifluoromethyl-pyridin-2-yloxy)-cyclohexylamine (80 mg, 0.31mmol). The reaction mixture was stirred at room temperature for 18hours, concentrated under reduced pressure and purified by flashchromatography with 3% methanol:dichloromethane to provide the titledcompound. MS (ESI) m/z 421 (M+H)⁺; ¹H NMR (DMSO) δ 8.58 (m, 1H), 8.06(m, 1H), 6.97 (d, 1H), 4.97 (m, 1H), 4.86 (m, 1H), 4.35 (m, 1H), 3.88(m, 1H), 3.19 (m, 2H), 2.15-2.40 (m, 9H), 1.55 (m, 4H).

Example 50(2S,5R)-5-ethynyl-1-(N-{4-trans(3-pyridin-4-yl-4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrileExample 50A 4-trans(3-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) inDMF (3 mL) at 0° C. was added 60% NaH in mineral oil (120 mg, 3 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then2-bromo-4-fluoro-1-(trifluoromethyl)benzene (0.17 ml, 1.2 mmol) wasadded. It was heated to 60° C. for 2 hours and stirred for 12 hours atroom temperature. The reaction mixture was diluted with ethyl acetateand washed with water (3 times) and brine. The organic layer was dried(sodium sulfate), filtered, and concentrated under reduced pressure toprovide the titled compound. MS (DCI) m/z 338 (M+H)⁺.

Example 50B(4-trans(3-bromo-4-trifluoromethyl-phenoxy)-cyclohexyl)-carbamic acidtert-butyl ester

To a cold solution (0° C.) of4-(3-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine (1 mmol) and NEt₃(0.42 ml, 3 mmol) in CH₂Cl₂ (5 mL) was added (Boc)₂O (261 mg, 1.2 mmol)in CH₂Cl₂ (1 mL) solution via syringe. The reaction mixture was stirredfrom 0° C. to room temperature for 2 hours. It was diluted with CH₂Cl₂and washed with water (2 times) and brine. The organic layer was dried(sodium sulfate), filtered, concentrated under reduced pressure andpurified by flash chromatography with 30% ethyl acetate/hexane toprovide the titled compound. MS (ESI) m/z 438 (M+H)⁺.

Example 5(4-trans(3-pyridin-4-yl-4-trifluoromethyl-phenoxy)-cyclohexyl)-carbamicacid tert-butyl ester

To a solution of(4-(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexyl)-carbamic acidtert-butyl ester (219 mg, 0.5 mmol) in isopropanol (3 mL) was added4-pyridylboronic acid (74 mg, 0.6 mmol), Pd(PPh₃)₂Cl₂ (35 mg, 0.05mmol), and K₂CO₃ (207 mg, 1.5 mmol). The reaction mixture was heated to85° C. for 3 hours. It was diluted with ethyl acetate and washed withwater (2 times) and brine. The organic layer was dried (sodium sulfate),filtered, concentrated under reduced pressure and purified by flashchromatography with 30% ethyl acetate/hexane to provide the titledcompound. MS (ESI) m/z 437 (M+H)⁺.

Example 50D4-trans(3-pyridin-4-yl-4-trifluoromethyl-phenoxy)-cyclohexylamine

To a solution of(4-(3-pyridin-4-yl-4-trifluoromethyl-phenoxy)-cyclohexyl)-carbamic acidtert-butyl ester (135 mg, 0.31 mmol) in CH₂Cl₂ (1 mL) was added 4NHCl/dioxane (3 ml). The reaction mixture was stirred at room temperaturefor 3 hours. It was concentrated under reduced pressure to provide thetitled compound. MS (ESI) m/z 337 (M+H)⁺.

Example 50(2S,5R)-5-ethynyl-1-(N-{4-trans(3-pyridin-4-yl-4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(3-pyridin-4-yl-4-trifluoromethyl-phenoxy)-cyclohexylamine (0.31mmol) and NEt₃ (0.063 ml, 0.45 mmol). The reaction mixture was stirredat room temperature for 18 hours, concentrated under reduced pressureand purified by flash chromatography with 3% methanol:dichloromethane toprovide the titled compound. MS (ESI) m/z 497 (M+H)⁺; ¹H NMR (CD₃OD) δ8.94 (d, 2H), 8.10 (d, 2H), 7.85 (d, 1H), 7.31 (m, 1H), 7.08 (d, 1H),4.94 (m, 1H), 4.85 (m, 1H), 3.18-3.25 (m, 4H), 2.20-2.50 (m, 9H), 1.65(m, 4H).

Example 51(2S,5R)-5-ethynyl-1-{N-(4-trans(pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrileExample 51A 4-trans(pyridin-2-yloxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (230 mg, 2 mmol) inDMF (10 mL) at 0° C. was added 60% NaH in mineral oil (240 mg, 6 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then2-bromo-pyridine (0.23 ml, 2.4 mmol) was added. It was heated to 60° C.for 2 hours and stirred for 12 hours at room temperature. The reactionmixture was diluted with ethyl acetate and washed with water (3 times)and brine. The organic layer was dried (sodium sulfate), filtered, andconcentrated under reduced pressure to provide the titled compound. MS(DCI) m/z 193 (M+H)⁺.

Example 51(2S,5R)-5-ethynyl-1-{N-(4-trans(pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(pyridin-2-yloxy)-cyclohexylamine (60 mg, 0.31 mmol). Thereaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 353 (M+H)⁺; ¹H NMR (CDCl₃) δ 8.13 (m, 1H), 7.54 (m, 1H), 6.82(m, 1H), 6.87 (d, 1H), 5.00 (m, 1H), 4.74 (m, 1H), 4.63 (m, 1H), 3.63(m, 2H), 2.29-2.60 (m, 4H), 2.19 (m, 2H), 2.00 (m, 2H), 1.72 (m, 2H),1.26-1.56 (m, 4H).

Example 52(2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(5-cyano-pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrileExample 52A 6-(4-Amino-4-transmethyl-cyclohexyloxy)-nicotinonitrile

Example 52A was prepared in the same manner as example 46A, bysubstituting 2-chloro-5-cyanopyridine for 3-fluoropyridine. MS (CT) m/z232 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 8.45 (t, 1H), 7.75 (dd, 1H),6.75 (d, 1H), 5.25-5.16 (m, 1H), 2.10-1.40 (m, 8H), 1.21 (s, 3H).

Example 52(2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(5-cyano-pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile

Example 52 was prepared in the same manner as example 46, bysubstituting example 52A for example 46A. MS (CI) m/z 392 (M+1)⁺; ¹H NMR(300 MHz, MeOH-d₄) δ ppm 8.52 (d, 1H), 7.96 (dd, 1H), 6.87 (d, 1H),5.20-5.10 (m, 1H), 4.90-4.80 (m, 1H), 4.20 (AB quartet, 2H), 3.24 (d,1H), 2.50-2.20 (m, 6H), 2.15-1.70 (m, 6H), 1.50 (s, 3H).

Example 53(2S,5R)-5-ethynyl-1-{N-(4-trans(pyrimidin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrileExample 53A 4-trans(pyrimidin-2-yloxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (230 mg, 2 mmol) inDMF (10 mL) at 0° C. was added 60% NaH in mineral oil (240 mg, 6 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then2-chloro-pyrimidine (275 mg, 2.4 mmol) was added. It was heated to 60°C. for 2 hours and stirred for 12 hours at room temperature. Thereaction mixture was diluted with ethyl acetate and washed with water (3times) and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated under reduced pressure to provide the titledcompound. MS (DCI) m/z 194 (M+H)⁺.

Example 53(2S,5R)-5-ethynyl-1-{N-(4-trans(pyrimidin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(pyrimidin-2-yloxy)-cyclohexylamine (60 mg, 0.31 mmol). Thereaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 353 (M+H)⁺; ¹H NMR (DMSO) δ 8.58 (d, 2H), 7.09 (m, 1H), 4.91(m, 1H), 4.75 (m, 1H), 3.57 (m, 1H), 3.52 (m, 2H), 2.20-2.38 (m, 3H);1.91-2.13 (m, 6H), 1.45 (m, 2H), 1.20 (m, 2H).

Example 54(2S,5R)-5-ethynyl-1-{N-(4-trans(5-cyano-pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrileExample 54A 6-(4-trans-aminocyclohexyloxy)-nicotinonitrile

To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) inDMF (6 mL) at 0° C. was added 60% NaH in mineral oil (120 mg, 3 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then2-chloro-5-cyanopyridine (151 mg, 1.25 mmol) was added. It was heated to60° C. for 2 hours and stirred for 12 hours at room temperature. Thereaction mixture was diluted with ethyl acetate and washed with water (3times) and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated under reduced pressure to provide the titledcompound. MS (DCI) m/z 218 (M+H)⁺.

Example 54(2S,5R)-5-ethynyl-1-{N-(4-trans(5-cyano-pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 6-(4-aminocyclohexyloxy)-nicotinonitrile (66 mg, 0.31 mmol). Thereaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 377 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 8.69 (m, 1H), 8.15 (m, 1H),6.96 (m, 1H), 4.99 (m, 1H), 4.86 (m, 1H), 4.35 (m, 1H), 3.88 (m, 1H),3.19 (m, 2H), 2.29 (m, 2H), 2.25 (d, 1H), 2.18 (m, 6H), 1.54 (m, 4H).

Example 55(2S,5R)-5-ethynyl-1-(N-{4-(4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrileExample 55A 4-trans(4-trifluoromethyl-phenoxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (230 mg, 2 mmol) inDMF (10 mL) at 0° C. was added 60% NaH in mineral oil (244 mg, 6 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then4-fluorobenzotrifluoride (0.32 ml, 2.5 mmol) was added. It was heated to60° C. for 2 hours and stirred for 12 hours at room temperature. Thereaction mixture was diluted with ethyl acetate and washed with water (3times) and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated under reduced pressure to provide the titledcompound. MS (DCI) m/z 260 (M+H)⁺.

Example 55(2S,5R)-5-ethynyl-1-(N-{4-(4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(4-trifluoromethyl-phenoxy)-cyclohexylamine (79 mg, 0.31 mmol).The reaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 420 (M+H)⁺; ¹H NMR (DMSO) δ 7.62 (d, 2H); 7.15 (d, 2H), 4.96(m, 1H), 4.86 (m, 1H), 4.39 (m, 2H), 3.90 (m, 1H), 3.18 (m, 1H), 2.52(m, 1H), 2.29 (m, 2H), 2.19 (d, 1H), 2.15 (m, 6H), 1.50 (m, 4H).

Example 56(2S,5R)-5-ethynyl-1-(N-{4-((5-fluoropyridin-3-yl)oxy)-1-methylcyclohexyl}glycyl)pyrrolidine-2-carbonitrile

Example 56 was prepared in the same manner as example 46, bysubstituting 3,5-difluoropyridine for 3-fluoropyridine. MS (ESI) m/z 385(M+H)⁺; ¹H NMR (CDCl₃) δ 8.13 (m, 1H); 8.08 (d, 1H); 6.94 (m, 1H); 4.75(m, 1H); 4.64 (m, 1H); 4.30 (m, 1H); 3.58 (m, 2H); 2.40 (m, 4H);1.65-2.04 (m, 7H); 1.45 (m, 2H); 1.14 (s, 3H).

Example 57(2S,5R)-5-ethynyl-1-(N-(4-trans(4-carboxy-phenoxy)cyclohexyl)glycyl)pyrrolidine-2-carbonitrileExample 57A 4-(4-trans-aminocyclohexyloxy)-benzoic acid tert-butyl ester

To a stirred solution of trans-4-aminocyclohexanol (345 mg, 3 mmol) inDMF (9 mL) at 0° C. was added 60% NaH in mineral oil (360 mg, 9 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then tert-butyl4-fluorobenzoate (706 mg, 3.6 mmol) was added. It was heated to 60° C.for 2 hours and stirred for 12 hours at room temperature. The reactionmixture was diluted with ethyl acetate and washed with water (3 times)and brine. The organic layer was dried (sodium sulfate), filtered, andconcentrated under reduced pressure to provide the titled compound. MS(DCI) m/z 292 (M+H)⁺.

Example 57B(2S,5R)-trans-4-{4-(2-(2-Cyano-5-ethynyl-pyrrolidin-1-yl)-2-oxo-ethylamino)-cyclohexyloxy}-benzoicacid tert-butyl ester

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(4-aminocyclohexyloxy)-benzoic acid tert-butyl ester (89 mg,0.31 mmol). The reaction mixture was stirred at room temperature for 18hours, concentrated under reduced pressure and purified by flashchromatography with 3% methanol/97% dichloromethane to provide thetitled compound. MS (ESI) m/z 452 (M+H)⁺; ¹H NMR (CDCl₃) δ 7.91 (d, 2H),6.86 (d, 2H), 4.74 (m, 1H), 4.60 (m, 1H), 4.28 (m, 1H), 3.64 (m, 2H),2.32-2.59 (m, 6H), 2.17 (m, 2H), 2.04 (m, 2H), 1.24-1.54 (m, 4H).

Example 57(2S,5R)-5-ethynyl-1-(N-(4-trans(4-carboxy-phenoxy)cyclohexyl)glycyl)pyrrolidine-2-carbonitrile

To a solution of Example 57B (40 mg, 0.088 mmol) in CH₂Cl₂ (0.5 mL) wasadded 4N HCl/dioxane (1 ml). The reaction mixture was stirred at roomtemperature for 3 hours. It was concentrated under reduced pressure toprovide the titled compound. MS (ESI) m/z 396 (M+H)⁺, ¹H NMR (MeOD) δ7.95 (d, 2H), 6.98 (d, 2H), 4.45 (m, 1H), 4.24 (m, 2H), 3.18 (m, 2H),2.20-2.45 (m, 6H); 1.50-1.74 (m, 4H).

Example 58(2S,5R)-5-ethynyl-1-(N-{4-(2-(2-oxopyrrolidin-1-yl)-4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrileExample 58A 4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) inDMF (3 mL) at 0° C. was added 60% NaH in mineral oil (120 mg, 3 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then3-bromo-4-fluoro-1-trifluoromethyl benzene (0.17 ml, 1.2 mmol) wasadded. It was heated to 60° C. for 2 hours and stirred for 12 hours atroom temperature. The reaction mixture was diluted with ethyl acetateand washed with water (3 times) and brine. The organic layer was dried(sodium sulfate), filtered, and concentrated under reduced pressure toprovide the titled compound. MS (DCI) m/z 338 (M+H)⁺.

Example 58B(4-trans(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexyl)-carbamic acidtert-butyl ester

To a cold solution (0° C.) of4-(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexylamine (1 mmol) and NEt₃(0.42 ml, 3 mmol) in CH₂Cl₂ (5 mL) was added (Boc)₂O (261 mg, 1.2 mmol)in CH₂Cl₂ (1 mL) solution via syringe. The reaction mixture was stirredfrom 0° C. to room temperature for 2 hours. It was diluted with CH₂Cl₂and washed with water (2 times) and brine. The organic layer was dried(sodium sulfate), filtered, concentrated under reduced pressure andpurified by flash chromatography with 30% ethyl acetate/hexane toprovide the titled compound. MS (ESI) m/z 438 (M+H)⁺.

Example 58C{4-trans(3-(2-oxo-pyrrolidin-1-yl)-4-trifluoromethyl-phenoxy)-cyclohexyl}-carbamicacid tert-butyl ester

To a cold solution of(4-(2-bromo-4-trifluoromethyl-phenoxy)-cyclohexyl)-carbamic acidtert-butyl ester (220 mg, 0.5 mmol) in pyridine (5 mL) was added2-pyrrolidinone (0.08 ml, 1 mmol), Cu powder (64 mg, 1 mmol), and K₂CO₃(414 mg, 3 mmol). The reaction mixture was heated to 85° C. for 16hours. It was diluted with ethyl acetate and washed with water (2 times)and brine. The organic layer was dried (sodium sulfate), filtered,concentrated under reduced pressure and purified by flash chromatographywith 50% ethyl acetate/hexane to provide the titled compound. MS (ESI)m/z 444 (M+H)⁺.

Example 58D1-(2-(4-trans-amino-cyclohexyloxy)-5-trifluoromethyl-phenyl)-pyrrolidine-2-one

To a solution of{4-(3-(2-oxo-pyrrolidin-1-yl)-4-trifluoromethyl-phenoxy)-cyclohexyl}-carbamicacid tert-butyl ester (80 mg, 0.18 mmol) in CH₂Cl₂ (1 mL) was added 4NHCl/dioxane (2 ml). The reaction mixture was stirred at room temperaturefor 3 hours. It was concentrated under reduced pressure to provide thetitled compound. MS (ESI) m/z 344 (M+H)⁺.

Example 58(2S,5R)-5-ethynyl-1-(N-{4-trans-(2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.024 g,0.12 mmol) in acetonitrile (1 mL) at room temperature was added1-(2-(4-amino-cyclohexyloxy)-5-trifluoromethyl-phenyl)-pyrrolidine-2-one(0.18 mmol) and NEt₃ (0.050 ml, 0.36 mmol). The reaction mixture wasstirred at room temperature for 18 hours, concentrated under reducedpressure and purified by flash chromatography with 3%methanol:dichloromethane to provide the titled compound. MS (ESI) m/z504 (M+H)⁺; ¹H NMR (CD₃OD) δ 7.62 (m, 1H), 7.59 (m, 1H), 7.30 (d, 1H),4.85 (m, 1H), 4.35 (m, 1H), 3.78 (m, 2H), 3.23 (m, 1H), 3.14 (m, 1H),2.53 (m, 2H), 2.44 (m, 2H), 2.20-2.33 (m, 7H), 1.62 (m, 4H).

Example 59(2S,5R)-1-{N-(4-trans(4-cyano-2-methoxyphenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrileExample 59A 4-(4-trans-amino-cyclohexyloxy)-3-methoxy-benzonitrile

To a stirred solution of trans-4-aminocyclohexanol (115 mg, 1 mmol) inDMF (5 mL) at 0° C. was added 60% NaH in mineral oil (120 mg, 3 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then4-fluoro-3-methoxy-benzonitrile (182 mg, 1.2 mmol) was added. It washeated to 60° C. for 2 hours and stirred for 12 hours at roomtemperature. The reaction mixture was diluted with ethyl acetate andwashed with water (3 times) and brine. The organic layer was dried(sodium sulfate), filtered, and concentrated under reduced pressure toprovide the titled compound. MS (DCI) m/z 247 (M+H)⁺.

Example 59(2S,5R)-1-{N-(4-trans(4-cyano-2-methoxyphenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(4-amino-cyclohexyloxy)-3-methoxy-benzonitrile (75 mg, 0.31mmol). The reaction mixture was stirred at room temperature for 18hours, concentrated under reduced pressure and purified by flashchromatography with 3% methanol:dichloromethane to provide the titledcompound. MS (ESI) m/z 407 (M+H)⁺; ¹H NMR (DMSO) δ 7.40 (s, 1H), 7.37(d, 1H), 7.25 (d, 1H), 4.95 (m, 1H), 4.84 (m, 1H), 4.39 (m, 2H), 3.90(m, 1H), 3.79 (s, 3H), 3.44 (m, 2H), 3.16 (m, 1H), 2.28 (m, 2H), 2.16(d, 1H), 2.13 (m, 6H), 1.53 (m, 4H).

Example 60(2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrileExample 60A 4-trans(5-chloro-pyridin-2-yloxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (230 mg, 2 mmol) inDMF (10 mL) at 0° C. was added 60% NaH in mineral oil (240 mg, 6 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then2,5-dichloro-pyridine (356 mg, 2.4 mmol) was added. It was heated to 60°C. for 2 hours and stirred for 12 hours at room temperature. Thereaction mixture was diluted with ethyl acetate and washed with water (3times) and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated under reduced pressure to provide the titledcompound. MS (DCI) m/z 227 (M+H)⁺.

Example 60(2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(5-chloro-pyridin-2-yloxy)-cyclohexylamine (70 mg, 0.31 mmol).The reaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 387 (M+H)⁺; ¹H NMR (CDCl₃) δ 8.07 (d, 1H), 7.49 (m, 1H); 6.63(d, 1H), 4.93 (m, 1H), 4.74 (m, 1H), 4.62 (m, 1H), 3.63 (m, 2H);2.31-2.59 (m, 6H); 2.15 (m, 2H), 1.71 (m, 2H); 1.30-1.54 (m, 4H).

Example 61(2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrileExample 61A 1-Methyl-4-trans(pyridin-2-yloxy)-cyclohexylamine

Example 61A was prepared in the same manner as example 46A, bysubstituting 2-chloropyridine for 3-fluoropyridine. MS (CI) m/z 207(M+1)⁺.

Example 61(2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile

Example 61 was prepared in the same manner as example 46, bysubstituting example 61A for example 46A. MS (CI) m/z 367 (M+1)⁺; ¹H NMR(300 MHz, MeOH-d₄) δ ppm 8.38-8.30 (m, 2H), 7.58 (d, 1H), 7.41 (t, 1H),5.10-4.98 (m, 1H), 4.95-4.90 (m, 1H), 4.23 (AB quartet, 2H), 3.24 (d,1H), 2.50-2.20 (m, 6H), 2.15-1.70 (m, 6H), 1.53 (s, 3H).

Example 62(2S,5R)-5-ethynyl-1-(N-{4-trans((5-fluoropyridin-3-yl)oxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrileExample 62A 4-trans(5-fluoro-pyridin-3-yloxy)cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (460 mg, 4 mmol) inDMF (5 mL) at 0° C. was added 60% NaH in mineral oil (480 mg, 12 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then3,5-difluoro-pyridine (560 mg, 4.8 mmol) was added. It was heated to 60°C. for 2 hours and stirred for 12 hours at room temperature. Thereaction mixture was diluted with ethyl acetate and washed with water (3times) and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated under reduced pressure to provide the titledcompound. MS (DCI) m/z 211 (M+H)⁺.

Example 62(2S,5R)-5-ethynyl-1-(N-{4-trans((5-fluoropyridin-3-yl)oxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(5-fluoro-pyridin-3-yloxy)cyclohexylamine (65 mg, 0.31 mmol).The reaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 371 (M+H)⁺; ¹H NMR (CD₃OD) δ 8.52 (s, 2H), 8.14 (d, 1H), 4.65(m, 1H), 4.34 (m, 1H), 4.17 (m, 1H), 3.35 (m, 2H), 3.21 (m, 1H),2.61-2.30 (m, 9H), 1.60-1.80 (m, 4H).

Example 63(2S,5R)-1-(N-{4-trans((5-bromopyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrileExample 63A 4-trans(5-bromo-pyridin-2-yloxy)-cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (345 mg, 3 mmol) inDMF (10 mL) at 0° C. was added 60% NaH in mineral oil (360 mg, 9 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then5-bromo-2-chloro-pyridine (700 mg, 3.6 mmol) was added. It was heated to60° C. for 2 hours and stirred for 12 hours at room temperature. Thereaction mixture was diluted with ethyl acetate and washed with water (3times) and brine. The organic layer was dried (sodium sulfate),filtered, and concentrated under reduced pressure to provide the titledcompound. MS (DCI) m/z 271 (M+H)⁺.

Example 63(2S,5R)-1-(N-{4-trans((5-bromopyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(5-bromo-pyridin-2-yloxy)-cyclohexylamine (84 mg, 0.31 mmol).The reaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 430 (M+H)⁺; ¹H NMR (CD₃OD) δ 8.19 (d, 1H), 7.80 (m, 1H), 6.72(d, 1H), 4.95 (m, 1H), 4.87 (m, 1H), 3.49 (m, 1H), 3.43 (m, 2H), 3.21(m, 1H), 2.37-2.47 (d, 3H), 2.20-2.36 (m, 6H), 1.60 (m, 4H).

Example 64(2S,5R)-5-ethynyl-1-{N-(4-trans(pyridin-3-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrileExample 64A 4-trans(pyridin-3-yloxy)cyclohexylamine

To a stirred solution of trans-4-aminocyclohexanol (230 mg, 2 mmol) inDMF (5 mL) at 0° C. was added 60% NaH in mineral oil (240 mg, 6 mmol).The reaction mixture was stirred at 0° C. for ½ hour and then3-fluoro-pyridine (0.21 ml, 2.4 mmol) was added. It was heated to 60° C.for 2 hours and stirred for 12 hours at room temperature. The reactionmixture was diluted with ethyl acetate and washed with water (3 times)and brine. The organic layer was dried (sodium sulfate), filtered, andconcentrated under reduced pressure to provide the titled compound. MS(DCI) m/z 193 (M+H)⁺.

Example 64(2S,5R)-5-ethynyl-1-{N-(4-trans(pyridin-3-yloxy)cyclohexy)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 4-(pyridin-3-yloxy)cyclohexylamine (59 mg, 0.31 mmol). Thereaction mixture was stirred at room temperature for 18 hours,concentrated under reduced pressure and purified by flash chromatographywith 3% methanol:dichloromethane to provide the titled compound. MS(ESI) m/z 353 (M+H)⁺; ¹H NMR (CDCl₃) δ 8.29 (s, 1H), 8.19 (m, 1H), 7.19(m, 2H), 4.74 (m, 1H), 4.60 (m, 1H), 4.25 (m, 1H), 3.63 (m, 2H),2.29-2.64 (m, 4H), 2.16 (m, 2H); 2.03 (m, 3H), 1.72 (m, 2H), 1.53 (m,2H), 1.32 (m, 2H).

Example 65(2S,5R)-5-ethynyl-1-(N-(1,1,3,3-tetramethylbutyl)glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g,0.20 mmol, Example 8D) in acetonitrile (3 mL) at room temperature undernitrogen was added 1,1,3,3-tetramethylbutylamine (0.066 g, 0.406 mmol).The reaction mixture was stirred for two days and then concentratedunder reduced pressure. The residue was flash chromatographed with 2%MeOH/CH₂Cl₂ to provide the titled compound. MS (DCI) m/z 290 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 1.5-2.02 (10H, m), 2.07-2.21 (2H, m), 2.45-2.50(2H, m), 3.03-3.5 (6 Hs), 3.76 (1H, d), 3.78-4.53 (2H, m), 4.53-4.55(1H, t), 5.06 (1H, m), 5.1 (1H, m).

Example 66(2S,5R)-1-{N-(1,1-dimethyl-2-(5-cyano-pyridin-2-yloxy)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrileExample 66A 6-(2-amino-2-methyl-propoxy)-nicotinonitrile

To a solution of 2-amino-2-methyl-1-propanol (0.5 ml, 5.60 mmol), in DMF(20 mL) was added NaH 60% (0.67 g, 16.80 mmol) and then6-chloronicotinonitrile (2.03 g, 11.22 mmol). The mixture heated to 70°C. for 2 hours and then stirred at room temperature overnight. Thereaction mixture was taken up in H₂O and extracted with EtOAc. Theorganic phase was washed with water (3×), dried over Na₂SO₄ andconcentrated under reduced pressure to provide the titled compound as apale yellow solid. MS (DCI) m/z 235 (M+H)⁺.

Example 66(2S,5R)-1-{N-(1,1-dimethyl-2-(5-cyano-pyridin-2-yloxy)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g,0.25 mmol, Example 8D) in acetonitrile (3 mL) at room temperature undernitrogen, was added 6-(2-amino-2-methyl-propoxy)-nicotinonitrile (0.1 g,0.508 mmol). The reaction mixture was stirred overnight and thenconcentrated under reduced pressure. The residue was flashchromatographed with 2% MeOH/CH₂Cl₂ to provide the desired compound as awhite solid. MS (DCI) m/z 352 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.01-2.04 (2H, m), 2.05 (2H, s), 2.07 (2H, s), 3.03 (1H, m), 3.04 (6H,s), 3.5-4.57 (2H, m), 4.57-4.58 (1H, m), 4.58-5.59 (1H, m), 7.0-7.08(3H, m).

Example 67(2S,5R)-1-(N-(tert-butyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g,0.203 mmol, Example 8D) in acetonitrile (3 mL) at room temperature undernitrogen was added tert-butylamine (0.043 ml, 0.406 mmol). The reactionmixture was stirred at ambient temperature overnight. The reactionmixture was concentrated under reduced pressure. The residue was flashchromatographed with 3% MeOH/CH₂Cl₂ to provide the desired compound as apale yellow oil. MS (DCI) m/z 234 (M+H)⁺.

The free base and 1 M HCl in ether were stirred at room temperature for2 h and then concentrated under reduced pressure. The residue wastriturated with diethyl ether to provide the desired hydrochloride saltas a white powder. ¹H NMR (DMSO-d₆) (major rotamer) δ 5.20 (m, 1H), 4.86(m, 1H), 4.33 (s, 1H), 3.78 (s, 1H), 3.76 (s, 1H), 2.45 (m, 1H), 2.26(m, 1H), 2.31 (m, 1H), 2.13 (m, 1H), 1.33 (s, 1H).

Example 68(2S,5R)-1-{N-(1,1-dimethyl-2-(quinolin-4-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

Example 68 was prepared using the same procedure as described forExample 155 substituting 6-chloronicotinonitrile with 4-chloroquinoline.MS (DCI/NH₃) m/z 376 (M+H)⁺.

Example 69(2S,5R)-5-ethynyl-1-{N-(2-(4-fluorophenyl)-1,1-dimethylethyl)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g,0.25 mmol, Example 8D) in acetonitrile (3 mL) at room temperature undernitrogen was added 1-(4-fluorophenyl)-2-methyl-2-propylamine (0.09 g,0.508 mmol). The reaction mixture was stirred for two days and thenconcentrated under reduced pressure. The residue was flashchromatographed with 1-2% MeOH/CH₂Cl₂ to provide the desired compound asa white powder. MS (DCI) m/z 328 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.01-2.04 (2H, m), 2.05 (2H, s), 2.07 (2H, s), 3.03 (1H, m), 3.04 (6H,s), 3.5-4.57 (2H, m), 4.57-4.58 (1H, m), 4.58-5.59 (1H, m), 7.0-7.03(4H, m).

Example 70(2S,5R)-1-(N-(1,1-dimethylpropyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.152 mmol, Example 8D) in acetonitrile (3 mL) at room temperature undernitrogen was added tert-amylamine (0.027 g, 0.228 mmol). The reactionmixture was stirred for two days and then concentrated under reducedpressure. The residue was flash chromatographed with 5% MeOH/CH₂Cl₂ toprovide the titled compound. MS (DCI) m/z 248 (M+H)⁺.

Example 71(2S,5R)-1-{N-(2-(1,3-benzothiazol-2-ylamino)-1,1-dimethylethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

Example 71 was prepared using the same procedure as described forExample 155 substituting 6-chloronicotinonitrile with2-chlorobenzothiazole. MS (DCI/NH₃) m/z 382 (M+H)⁺.

Example 74(2S,5R)-1-(N-1-adamantylglycyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g,0.20 mmol) in acetonitrile (3 mL) at room temperature under nitrogen wasadded 1-adamantanamine (0.06 g, 0.408 mmol). The reaction mixture wasstirred for two days and then concentrated under reduced pressure. Theresidue was flash chromatographed with 2% MeOH/CH₂Cl₂ to provide thetitled compound. MS (DCI) m/z 312 (M+H)⁺.

Example 75(2S,5R)-1-(N-cyclohexylglycyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.035 g,0.178 mmol, Example 8D) in acetonitrile (3 mL) at room temperature undernitrogen was added cyclohexylamine (0.041 ml, 0.356 mmol), The reactionmixture was stirred at room temperature overnight and then concentratedunder reduced pressure. The residue was flash chromatographed with 2-3%MeOH/CH₂Cl₂ to provide the desired compound as a pale yellow oil. MS(DCI) m/z 260 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 1.5-2 (10H, m), 2.13-2.31(2H, m), 2.41-2.48 (2H, m), 3.76 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55(1H, t), 4.9 (1H, m), 5.05 (1H, m).

Example 76(2S,5R)-5-ethynyl-1-{N-(1-(methoxymethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrileExample 76A (1-hydroxymethyl-cyclopentyl)-carbamic acid benzyl ester

To a stirred solution of 1-amino-1-cyclopentanemethanol (1.15 g, 10mmol) and NaHCO₃ (0.84 g, 10 mmol) in acetone (14 mL)/water (14 ml) atroom temperature was added benzyl succinimidyl carbonate (2.5 g, 10mmol). The reaction mixture was stirred at room temperature for 18hours, concentrated under reduced pressure and purified by flashchromatography with 3% methanol:dichloromethane to provide the titledcompound. MS (DCI) m/z 250 (M+H)⁺.

Example 76B (1-methoxymethyl-cyclopentyl)-carbamic acid benzyl ester

To a cold solution (0° C.) of (1-hydroxymethyl-cyclopentyl)-carbamicacid benzyl ester (250 mg, 1 mmol) and 48% aqueous HBF₄ (0.13 ml, 1mmol) in CH₂Cl₂ (4 mL) was added TMSCHN₂ (2N in hexane, 2 mL, 4 mmol)via syringe. The resulting mixture was stirred, at 0° C., for ½ hourfollowed by the addition of water (10 mL). The aqueous mixture wasextracted with CH₂Cl₂ (2×50 mL), and the combined organic layers weredried (sodium sulfate), filtered, concentrated and chromatographed with30% ethyl acetate/hexane to provide the titled compound. MS (DCI) m/e264 (M+H)⁺.

Example 76C 1-methoxymethyl-cyclopentylamine

To a solution of (1-methoxymethyl-cyclopentyl)-carbamic acid benzylester (150 mg, 0.57 mmol) in MeOH (5 mL) was added HCO₂NH₄ (216 mg, 3.42mmol), followed by Pd/C (10%, 6 mg, 0.057 mmol). The resulting mixturewas heated, to 70° C., for 2 hours. The reaction mixture was filteredand concentrated to provide the titled compound. MS (DCI) m/e 130(M+H)⁺.

Example 76(2S,5R)-5-ethynyl-1-{N-(1-(methoxymethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.018 g,0.09 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 1-methoxymethyl-cyclopentylamine (17 mg, 0.13 mmol). The reactionmixture was stirred at room temperature for 18 hours, concentrated underreduced pressure and purified by flash chromatography with 3%methanol:dichloromethane to provide the titled compound. MS (ESI) m/z290 (M+H)⁺; ¹H NMR (CD₃OD) δ 4.84 (m, 2H), 3.48 (m, 2H), 3.41 (s, 3H),3.31 (m, 2H), 2.43 (d, 1H), 2.30-2.48 (m, 4H), 1.72-1.96 (m, 8H).

Example 77(2S,5R)-5-ethynyl-1-(N-tetrahydro-2H-pyran-4-ylglycyl)pyrrolidine-2-carbonitrile

Example 77 was prepared in the same manner as Example 46, bysubstituting tetrahydro-pyran-4-ylamine for Example 46A. MS (CI) m/z 262(M+1)⁺.

Example 78(2S,5R)-5-ethynyl-1-{N-((2S)-2-hydroxycyclopentyl)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.040 g,0.20 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded trans-2-aminocyclopentanol hydrochloride (56 mg, 0.41 mmol) andtriethylamine (0.14 ml, 1.02 mmol). The reaction mixture was stirred atroom temperature for 18 hours, concentrated under reduced pressure andpurified by flash chromatography with 3% methanol:dichloromethane toprovide the titled compound. MS (ESI) m/z 262 (M+H)+; ¹H NMR (MeOH) 4.79(m, 1H), 4.17-4.40 (m, 3H), 3.18 (m, 1H), 2.48 (m, 4H); 2.00-2.30 (m,4H), 1.80 (m, 2H), 1.66 (2H, m).

Example 79(2S,5R)-1-(N-cyclopentylglycyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g,0.203 mmol, Example 8D) in acetonitrile (3 mL) at ambient temperatureunder nitrogen was added cyclopentylamine (0.04 ml, 0.406 mmol). Thereaction mixture was stirred at room temperature overnight and thenconcentrated under reduced pressure. The residue was flashchromatographed with 3% MeOH/CH₂Cl₂ to provide the desired compound as apale yellow oil. MS (DCI) m/z 246 (M+H)⁺; ¹H NMR (300 MHz, DMSO) δ 1.5-2(8H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5(2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m).

Example 80(2S,5R)-5-ethynyl-1-{N-(1-(hydroxymethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.030 g,0.15 mmol, Example 8D) in acetonitrile (1 mL) at room temperature wasadded 1-amino-1-cyclopentanemethanol (35 mg, 0.31 mmol). The reactionmixture was stirred at room temperature for 18 hours, concentrated underreduced pressure and purified by flash chromatography with 3%methanol:dichloromethane to provide the titled compound. MS (ESI) m/z276 (M+H)⁺; ¹H NMR (DMSO) δ 4.99 (m, 1H), 4.86 (t, 1H), 4.28 (m, 1H),4.00 (m, 1H), 3.50 (d, 2H), 3.51 (m, 2H), 2.27 (m, 2H), 2.14 (m, 1H),1.75 (m, 6H), 1.55 (m, 2H).

Example 84(2S,5S)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-methylpyrrolidine-2-carbonitrileExample 84A 5-Methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester

The ethyl (5S)-5-methyl-L-prolinate was prepared as the trifluoroaceticacid salt as described in Example 6 by substituting methyl magnesiumbromide for ethyl magnesiumbromide. Ethyl (5S)-5-methyl-L-prolinatetrifluoroacetic acid salt (18.08 mmol), triethyl amine (36.16 mmol) andDMAP (0.906 mmol) were mixed in 40 mL of dichloromethane and then cooledto 0° C. Boc₂O (19.89 mmol) was added and the mixture was stirredovernight. The mixture was then diluted with dichloromethane, washedwith 1N HCl and then with saturated NaHCO₃ solution. The organic layerwas dried with Na₂SO₄, and then concentrated. The crude product waspurified by chromatography (silica gel, 50% then 75-80% EtOAc/hexane) togive the desired titled compound. MS (CI) m/z+258 (M+H)⁺. (α)²⁰_(D)=−35.9 (c 1.45, MeOH).

Example 84B (2S,5S)-5-Methyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester

Example 84A (3.69 g, 14.34 mmol) in 15 mL of EtOH was treated with 14.3mL of 1.7 N LiOH solution at room temperature. After 4 h, the mixturewas concentrated, acidified with 1N HCl and then extracted with EtOAc(3×). The combined organic extracts were dried with Na₂SO₄, and thenconcentrated to give the crude acid. MS (ESI) m/z 228 (M−H)⁻.

Example 84C (2S,5S)-2-Carbamoyl-5-methyl-pyrrolidine-1-carboxylic acidtert-butyl ester

Example 84B (2.055 g, 8.96 mmol) and Et₃N (2.24 mL, 1.8 equiv.) weremixed in 15 mL of THF and then cooled to 0° C. Isobutyl chloroformate(1.51 mL, 1.3 equiv.) was added. After stirring for 35 min, 0.5 M NH₃ indioxane (35.8 mL, 2 equiv.) was added. After stirring at 0° C. for 3 h,the mixture was warmed to room temperature and stirred overnight. Thevolatiles were evaporated, and 1N HCl was added. The mixture wasextracted with EtOAc (3×). The combined organic extracts were dried withNa₂SO₄ and then concentrated. The crude product was purified bychromatography (silica gel, 50% then 75-80% EtOAc/hexane) to give thedesired amide. MS (ESI) m/z 229 (M+H)⁺.

Example 84D (2S,5S)-5-Methyl-pyrrolidine-2-carboxylic acid amidetrifluoroacetate

Example 84C (2.03 g, 8.89 mmol) in 4 mL of CH₂Cl₂ was treated with 6 mLof TFA at room temperature. After stirring for 5 h, toluene was added toazotrope off all the volatiles to afford the crude amine. MS (CI) m/z129 (M+H)⁺.

Example 84E((1S)-2-((2S,5S)-2-Carbamoyl-5-methyl-pyrrolidin-1-yl)-1-cyclopentyl-2-oxo-ethyl)-carbamicacid tert-butyl ester

Example 84D (296 mg, 0.66 mmol),L-tert-butoxycarbonylamino-cyclopentyl-acetic acid dicyclohexylaminesalt (308 mg, 0.726 mmol), and TBTU (275 mg, 0.858 mmol) were mixed in2.5 mL of DMF. Then 0.275 mL of NEt₃ (1.98 mmol) were added.Approximately another 0.1 mL of NEt₃ was added until the pH of themixture reached 6-7 (by wet pH paper). The mixture was stirred for 10 h,then purified by reverse-phase HPLC to give the desired amide (195 mg,84%). (ESI) m/z 354 (M+H)⁺.

Example 84E((1S)-2-((2S,5S)-2-Cyano-5-methyl-pyrrolidin-1-yl)-1-cyclopentyl-2-oxo-ethyl)-carbamicacid tert-butyl ester

The dehydration of the above amide was performed in a similar manner asdescribed in Example 6G to provide the desired nitrile. MS (ESI) m/z 336(M+H)⁺.

Example 84(2S,5S)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-methylpyrrolidine-2-carbonitrile

The removal of Boc group was performed in a similar manner as describedin Example 6 to give the title compound. ¹H NMR (400 MHz, MeOH-d₄) δ1.37 (d, J=6.75 Hz, 3H) 1.43 (m, 2H) 1.6-1.8 (m, 6H) 1.90 (m, 1H) 2.13(ddd, J=12.12, 7.36, 4.76 Hz, 1H) 2.39 (m, 4H) 4.11 (d, J=8.29 Hz, 1H)4.40 (m, 1H) 4.78 (t, J=8.44 Hz, 1H) ppm. MS (ESI) m/z 236 (M+H)⁺.

Example 85(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-prop-1-ynylpyrrolidine-2-carbonitrileExample 85A dimethyl(2S,5R)-5-propynyl-pyrrolidine-1,2-dicarboxylate

To a cold −45° C. solution ofdimethyl(2S)-5-methoxypyrrolidine-1,2-dicarboxylate (10 g, 46.08 mmol,Example 1B) and trimethylsilylpropyne (14.24 ml, 92.16 mmol, 2.0 equiv)in methylene chloride (180 mL) was added a solution of tin (IV) chloride(1 M in methylene chloride, 60.0 mL, 60.0 mmol, 1.3 equiv) dropwise viaan addition funnel over 30 minutes. To the dark yellow solution wasadded solid aluminum chloride (8.58 g, 64.52 mmol, 1.4 equiv) in oneportion. The resulting mixture was allowed to warm to room temperatureand stirred at room temperature for 48 hours. The reaction mixture wascarefully quenched by saturated aqueous NH₄OH (100 mL) with ice cooling.A white precipitate formed and was removed by filtration. The crudeproduct was obtained after concentration. The residue waschromatographed on a Biotage flash 40 M eluting with 70% hexane/30%ethyl acetate to afford the titled compound. MS (DCI/NH₃) m/e 226(M+H)⁺.

Example 85B methyl (5R)-5-propynyl-L-prolinate

A solution of dimethyl(2S,5R)-5-propynyl-pyrrolidine-1,2-dicarboxylate(4.25 g, 18.90 mmol) and iodotrimethylsilane (3.23 mL, 22.7 mmol,Example 85A) in chloroform (60 mL) was heated to 65° C. for 3 hours, wascooled to room temperature, concentrated under reduced pressure andflash chromatographed with 35% ethyl acetate/65% hexane to provide thetitled compound. MS (DCI/NH₃) m/e 168 (M+H)⁺.

Example 85CMethyl-N-(tert-butoxycarbonyl)-cyclopentyl-L-glycyl-(5R)-5-propynyl-L-prolinate

To a solution of methyl (5R)-5-propynyl-L-prolinate (334 mg, 2 mmol),dimethylaminopyridine (244 mg, 2 mmol), N-methylmorpholine (0.33 mL, 3mmol), and Boc-cyclopentyl-L-glycine.dicyclohexylamine (1.02 g, 2.4mmol) in dichloromethane (10 mL) at room temperature was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (383 g, 2.4mmol). The resulting mixture was stirred 16 hours at room temperature,and partitioned between ethyl acetate (100 mL) and 1 MHO (20 mL). Theaqueous layer was further extracted with ethyl acetate (100 mL). Thecombined organic layers were dried (sodium sulfate), filtered, andconcentrated. The residue was chromatographed with 70% ethylacetate/hexane provide the titled compound (67%). MS (ESI) m/e 393(M+H)⁺.

Example 85DN-(tert-butoxycarbonyl)-cyclopentyl-L-glycyl-(5R)-5-propynyl-L-proline

To a solution of methylN-(tert-butoxycarbonyl)-cyclopentyl-L-glycyl-(5R)-5-propynyl-L-prolinate(1.34 g, 3.42 mmol) in THF (10 mL)/water (5 ml) at room temperature wasadded lithium hydroxide (358 mg, 7.52 mmol). The resulting mixture wasstirred at room temperature for 6 hours. The reaction was diluted with 1M HCl solution, and the aqueous mixture was extracted with ethyl acetate(3×10 mL). The combined organic layers were dried (sodium sulfate),filtered, and concentrated to provide the titled compound. MS (ESI) m/e379 (M+H)⁺.

Example 85EN-(tert-butoxycarbonyl)-cyclopentyl-L-glycyl-(5R)-5-propynyl-L-prolinamide

To a cold (0° C.) solution ofN-(tert-butoxycarbonyl)-cyclopentyl-L-glycyl-(5R)-5-propynyl-L-proline(3.42 mmol) and N-methyl morpholine (0.44 mL, 3.94 mmol) in THF (15 mL)was added isobutyl chloroformate (0.56 mL, 4.26 mmol). The resultingcloudy white mixture was stirred at 0° C. for 30 minutes followed by theaddition of a solution of ammonia (0.5 M in dioxane, 19.7 mL, 9.84mmol). The solution was allowed to warm to room temperature and stirredfor 16 hours. The reaction mixture was diluted by the addition of 1 MHCl (50 mL), and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were dried (sodium sulfate), filtered, and concentratedto provide the crude compound. The residue was chromatographed with 95%CH₂Cl₂/MeOH to provide the titled compound. MS (ESI) m/e 378 (M+H)⁺.

Example 85FN-(tert-butoxycarbonyl)-cyclopentyl-L-glycyl-(5R)-5-propynyl-L-pyrrolidine-2-carbonitrile

To a cold solution (−35° C.) ofN-(tert-butoxycarbonyl)-cyclopentyl-L-glycyl-(5R)-5-propynyl-L-prolinamide(280 mg, 0.743 mmol) and imidazole (51 mg, 0.743 mmol) in pyridine (6mL) was added POCl₃ (0.14 mL, 1.49 mmol) via syringe. The resultingmixture was stirred, maintaining the temperature below −20° C., for 1hour followed by the addition of 1 M HCl (10 mL). The aqueous mixturewas extracted with ethyl acetate (3×50 mL), and the combined organiclayers were dried (sodium sulfate), filtered, concentrated andchromatographed with 30% ethyl acetate/hexane to provide the titledcompound. MS (ESI) m/e 348 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 5.15(t, 1H), 4.95 (d, 1H), 4.71 (t, 1H), 4.53 (ddd, 1H), 2.50 (d, 1H),2.50-2.28 (m, 4H), 1.75-1.57 (m, 3H).

Example 85(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile

To a solution ofN-(tert-butoxycarbonyl)-cyclopentyl-L-glycyl-(5R)-5-propynyl-L-pyrrolidine-2-carbonitrile(490 mg) in ether (1 mL) was added 4 M HCl in dioxane (8 mL). Theresulting mixture was stirred at room temperature for 2 hours and thesolvents removed under reduced pressure. The white solid was trituratedwith ether to provide the titled compound. MS (ESI) m/e 260 (M+H)⁺; ¹HNMR (DMSO) δ ppm 5.16 (m, 1H), 4.73 (m, 1H), 4.04 (m, 1H), 3.42 (m, 1H),2.03-2.47 (m, 4H), 1.85 (d, 3H), 1.39-1.70 (8H, m).

Example 86(2S,5R)-5-prop-1-ynyl-1-(N-{4-(4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.030 g,0.15 mmol, Example 88D) in acetonitrile (1 mL) at room temperature wasadded 4-(4-trifluoromethyl-phenoxy)-cyclohexylamine (79 mg, 0.31 mmol,Example 55A). The reaction mixture was stirred at room temperature for18 hours, concentrated under reduced pressure and purified by flashchromatography with 3% methanol:dichloromethane to provide the titledcompound. MS (ESI) m/z 434 (M+H)⁺; ¹H NMR (DMSO) δ ppm 7.63 (d, 2H),7.15 (d, 2H), 4.86 (m, 1H), 4.20-4.41 (m, 2H), 3.94 (m, 1H), 2.09-2.43(m, 8H), 1.88 (d, 3H), 1.41-1.65 (m, 4H).

Example 87(2S,5R)-1-{N-(1-(hydroxymethyl)cyclopentyl)glycyl}-5-prop-1-ynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.03 g,0.14 mmol, Example 88D) in acetonitrile (1 mL) at room temperature wasadded 1-amino-1-cyclopentanemethanol (35 mg, 0.28 mmol). The reactionmixture was stirred at room temperature for 18 hours, concentrated underreduced pressure and purified by flash chromatography with 3%methanol/97% dichloromethane to provide the titled compound. MS (ESI)m/z 290 (M+H)⁺; ¹H NMR (DMSO) δ ppm 4.86 (m, 1H), 4.16 (m, 1H), 3.52 (m,2H), 3.44 (m, 2H), 2.06-2.39 (m, 4H), 1.96 (m, 2H), 1.86 (d, 3H), 1.75(m, 6H), 1.56 (m, 2H).

Example 88(2S,5R)-1-(N-cyclopentylglycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrileExample 88A methyl (5R)-1-(chloroacetyl)-5-propynyl-L-prolinate

To a stirred solution of methyl (5R)-5-propynyl)-L-prolinate (1.5 g,8.98 mmol, Example 85B) and triethylamine (1.87 mL, 13.47 mmol) in drytetrahydrofuran (20 mL) at 0° C. was gradually added chloroacetylchloride (0.86 mL, 10.78 mmol). After stirring at room temperature for 2hours, the mixture was filtered. The solid cake was washed with THF, andthe filtrate and washings were combined, dried over sodium sulfate andconcentrated under reduced pressure. The residue taken up in toluene andconcentrated to dryness under reduced pressure to provide the titledcompound. MS (DCI) m/z 244 (M+H)⁺.

Example 88B (5R)-1-(chloroacetyl)-5-propynyl-L-proline

To a stirred solution of methyl(5R)-1-(chloroacetyl)-5-propynyl)-L-prolinate (1.26 g, 5.19 mmol) in THF(12 mL) and H₂O (6 mL) at room temperature was added LiOH.H₂O (326 mg,7.78 mmol). The reaction mixture was stirred at ambient temperatureovernight and concentrated under reduced pressure. The reaction mixturewas acidified to pH˜3 by adding 1M HCl dropwise. The solution wasextracted with ethyl acetate (3×). Combined ethyl acetate layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure to provide the titled compound. MS (DCI) m/z 230(M+H)⁺.

Example 88C (5R)-1-(chloroacetyl)-5-propynyl-L-prolinamide

To a stirred solution of (5R)-1-(chloroacetyl)-5-propynyl-L-proline(1.10 g, 4.8 mmol) in CH₂Cl₂ (24 mL) at −15° C. under nitrogen was added4-methylmorpholine (0.64 mL, 5.76 mmol), and then isobutyl chloroformate(0.81 mL, 6.24 mmol) over 10 minutes. A white precipitate formed. Thereaction mixture was stirred at −15° C. under nitrogen for 30 minutes,and a solution of NH₃ in dioxane (0.5 M, 29 mL, 14.4 mmol) was added.The reaction mixture was stirred at −15° C. for 30 minutes, warmed toroom temperature, and stirred at that temperature for 16 hours. Thereaction mixture was diluted with 1M HCl to pH 4 and extracted withethyl acetate (3×). The extracts were combined, washed with brine, dried(Na₂SO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography (60-75% ethyl acetate/hexane) providedthe titled compound. MS (DCI) m/z 229 (M+H)⁺.

Example 88D(2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile

To a stirred solution of (5R)-1-(chloroacetyl)-5-propynyl-L-prolinamide(0.28 g, 1.23 mmol) and imidazole (0.084 g, 1.23 mmol) in dry pyridine(6 mL) at −35° C. under nitrogen was added POCl₃ (0.23 mL, 2.46 mmol)dropwise. The reaction mixture was stirred between −35° C. to −15° C.for 1 hour and evaporated. The residue was diluted with dichloromethaneand washed with H₂O (2×), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. Purification by flash chromatography (10% ethylacetate/hexane) provided the titled compound. MS (DCI) m/z 211 (M+H)⁺.

Example 88(2S,5R)-1-(N-cyclopentylglycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-propynylpyrrolidine-2-carbonitrile (0.018 g,0.086 mmol) in acetonitrile (1 mL) at room temperature was addedcyclopentyl amine (0.017 mL, 0.17 mmol). The reaction mixture wasstirred at room temperature for 18 hours, concentrated under reducedpressure and purified by flash chromatography with 3% methanol/97%dichloromethane to provide the titled compound. MS (ESI) m/z 260 (M+H)⁺;¹H NMR (DMSO) δ ppm 4.89 (m, 1H), 4.84 (m, 1H), 4.07-4.13 (m, 2H), 3.52(m, 1H), 2.05-2.42 (m, 4H), 1.96 (m, 2H), 1.87 (d, 3H), 1.70 (m, 4H),1.52 (m, 2H).

Example 91(2S,5S)-1-(N-cyclopentylglycyl)-5-methylpyrrolidine-2-carbonitrileExample 91A(2S,5S)-1-(2-Chloro-acetyl)-5-methyl-pyrrolidine-2-carboxylic acid amide

(2S,5S)-5-Methyl-pyrrolidine-2-carboxylic acid amide trifluoroacetate(2.0 g, 8.2 mmol, Example 84D) and triethyl amine (1.9 mL, 24.6 mmol)were dissolved in CH₂Cl₂ (6 mL), and the mixture was cooled to 0° C.Chloroacetyl chloride (0.39 mL, 9.0 mmol) was added slowly via syringe.After 2 h, saturated NaHCO₃ was added, and the mixture was extractedwith EtOAc (3×). The combined organic extracts were dried (Na₂SO₄),concentrated and purified by flash chromatography (10% MeOH/EtOAc) togive the title compound. MS (DCI) m/z 205 (M+H)⁺.

Example 91B(2S,5S)-1-(2-Chloro-acetyl)-5-methyl-pyrrolidine-2-carbonitrile

(2S,5S)-1-(2-Chloro-acetyl)-5-methyl-pyrrolidine-2-carboxylic acid amide(0.25 g, 1.2 mmol) and imidazole (85 mg, 1.25 mmol) ware mixed inpyridine (5 mL). The mixture was cooled to −35° C. and POCl₃ (0.18 mL,1.8 mmol) was added slowly. The mixture was stirred at −35° C. for 1 h.Saturated NH₄Cl (20 mL) was added, and the mixture was extracted withEtOAc (3×). The combined organic layers were dried (Na₂SO₄), filteredand concentrated under reduced pressure. The oil was purified by flashchromatography (hexane:EtOAC, 2:1) to yield the title compound. MS (DCI)m/z 187 (M+H)⁺.

Example 91(2S,5S)-1-(N-cyclopentylglycyl)-5-methylpyrrolidine-2-carbonitrile

(2S,5S)-1-(2-Chloro-acetyl)-5-methyl-pyrrolidine-2-carbonitrile (50 mg,0.30 mmol) and cyclopentylamine (0.059 mL, 0.6 mmol) were dissolved inacetonitrile (2 mL) and stirred overnight. The product was purified byreverse phase HPLC eluting with 0% to 70% acetonitrile/0.1% aqueoustrifluoroacetic acid. ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.36 (d,J=6.44 Hz, 3H), 1.68 (m, 5H), 1.85 (m, 3H), 2.16 (m, 3H), 2.38 (m, 3H),3.60 (m, 1H), 4.20 (m, 1H), 4.77 (m, 1H). MS (ESI) m/z 236 (M+H)⁺.

Example 92(2S,5S)-4,4-difluoro-5-methyl-1-L-valylpyrrolidine-2-carbonitrile

This compound was prepared from 51 mg (0.23 mmol) of(S)—N-tert-butoxycarbonylvaline and 50 mg (0.23 mmol) of (2,5-cis)4,4-difluoro-5-methyl-pyrrolidine-2-carboxylic acid methyl esterhydrochloride (Example 95G) according to the same five step sequence asfor (2S,5S)-4,4-difluoro-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile(example 95H through example 95L) to give the titled compound as acolorless foam. ¹H NMR (500 MHz, DMSO-d₆) (mixture of rotamers, majorrotamer only) δ ppm 0.99 (m, 6H) 1.37 (m, 3H) 2.11 (m, 1H) 2.96 (m, 1H)3.09 (m, 1H) 4.09 (bs, 1H) 4.65 (m, 1H) 5.06 (t, J=8.6 Hz, 1H) 8.31 (bs,3H) MS (ESI) m/z=246 (M+H)⁺.

Example 94(2S,5S)-1-{N-(1-(hydroxymethyl)cyclopentyl)glycyl}-5-methylpyrrolidine-2-carbonitrile

The title compound was prepared using the conditions described inExample 91 substituting 1-amino-1-cyclopentanemethanol forcyclopentylamine. ¹H NMR (300 MHz, methanol-d₄) δ ppm 1.38 (d, J=6.44Hz, 3H), 1.80 (m, 8H), 2.32 (m, 2H), 3.29 (m, 4H), 3.62 (s, 2H), 3.96(m, 1H), 4.20 (m, 1H), 4.77 (m, 1H). MS (ESI) m/z 266 (M+H)⁺.

Example 95(2S,5S)-4,4-difluoro-1-L-leucyl-5-methylpyrrolidine-2-carbonitrileExample 95A Dibenyzyl Fumarate

To 13.92 g (120 mmol) of fumaric acid was added 250 mL of toluene and41.8 mL (240 mmol) of N,N-diethylisopropylamine. The mixture was stirreduntil only a small amount of solid was present, then 28.5 mL (240 mmol)of benzyl bromide was added. The reaction was stirred at 80° C. for 5 h,then it was cooled and extracted with water (1×50 mL), 1M HCl_((aq))(2×50 mL), saturated NaHCO_(3(aq)), and brine (1×50 mL), dried overMgSO₄, filtered, and concentrated to a solid. This was recrystallizedfrom 75 mL of hexanes to give the titled compound as colorless crystals.¹H NMR (300 MHz, DMSO-d₆) δ ppm 5.24 (s, 4H) 6.86 (s, 2H) 7.38 (m, 10H).

Example 95B (R)—N-tert-butoxycarbonylalanine benzyl ester

To a solution of 11.19 g (59.1 mmol) of (R)—N-tert-butoxycarbonylalaninein 70 mL of N,N-dimethylformamide was added 6.7 g (48.5 mmol) of K₂CO₃,and 6.9 mL (58.0 mmol) of benzyl bromide. The reaction was stirred at80° C. for 40 min, then poured into 350 mL of H₂O. The aqueous mixturewas extracted with diethyl ether (3×50 mL), then the combined etherlayers were back extracted with H₂O (2×50 mL), and brine (1×50 mL),dried over MgSO₄, filtered, and concentrated in vacuo to furnish thetitled compound as a colorless oil. MS (ESI) m/z=280 (M+H)⁺, 297(M+NH₄)⁺, 302 (M+Na)⁺: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.25 (d, J=7.5Hz, 3H) 1.37 (s, 9H) 4.06 (m, 1H) 5.07 (d, J=12.9 Hz, 1H) 5.15 (d,J=12.5 Hz, 1H) 7.34 (m, 6H).

Example 95C 5-Methyl-4-oxo-pyrrolidine-1,2,3-tricarboxylic acid2,3-dibenzyl ester 1-tert-butyl ester

To a solution of 5.59 g (20.0 mmol) of (R)—N-tert-butoxycarbonylalaninebenzyl ester and 5.92 g (20.0 mmol) of dibenzyl fumarate in 60 mL oftoluene was added 1.60 g (40 mmol) of 60% NaH in mineral oil. Thereaction was stirred at ambient temperature under N₂ for 24 h, thendiluted with 300 mL of diethyl ether. The solution was extracted with 1MHCl_((aq.)) (1×50 mL), saturated NaHCO_(3(aq.)) (3×50 mL), and brine(1×50 mL), dried over MgSO₄, filtered, and concentrated to provide thetitled compound as an oil.

Example 95D 5-Methyl-4-oxo-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester

To a suspension of 600 mg of 10% Pd—C in 25 mL of 2-propanol was added asolution of 8.9 g of crude5-methyl-4-oxo-pyrrolidine-1,2,3-tricarboxylic acid 2,3-dibenzyl ester1-tert-butyl ester in 100 mL of 2-propanol. The reaction was shakenunder 60 psi of H₂ for 1.5 h, then filtered and concentrated to an oil.This was taken up in 20 mL of 2M NaOH_((aq.)) and extracted with diethylether (3×15 mL) to remove the mineral oil introduced in the previousstep. The ether layers were set aside, and the aqueous layer was cooledwith an ice bath, then acidified with 10 mL of 6M HCl_((aq.)). Thesuspension was extracted with diethyl ether (3×15 mL), then the etherlayers were extracted with brine (1×15 mL), dried over MgSO₄, filtered,and concentrated to an oil.

Example 95E 5-Methyl-4-oxo-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester

To a solution of 3.0 g of crude5-methyl-4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in25 mL of N,N-dimethylformamide was added 1.2 g (8.7 mmol) of K₂CO₃, and1.2 mL (19.3 mmol) of methyl iodide. The mixture was stirred at 80° C.for 20 min, cooled to ambient temperature, then diluted with 125 mL of0.2M HCl_((aq.)). This was extracted with diethyl ether (3×20 mL), thenthe combined ether layers were extracted with water (1×20 mL), and brine(1×20 mL), dried over MgSO₄, filtered, and concentrated to an oil. Theproduct was purified via silica gel chromatography, eluting with 20%ethyl acetate/hexanes to give the 2,5-cis isomer. The 2,5-trans isomereluted slightly faster than the desired cis isomer. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.30 (d, J=7.1 Hz, 3H) 1.40 (m, 9H) 2.59 (dd, J=19.2, 3.2Hz, 1H) 3.12 (dd, J=18.3, 11.2 Hz, 1H) 3.66 (s, 3H) 3.92 (q, J=6.8 Hz,1H) 4.63 (dd, J=10.7, 3.6 Hz, 1H), NOE observed between H-2 and H-5, notobserved in the corresponding trans isomer; MS (ESI) m/z=256 (M−H)⁺.

Example 95F (2,5-cis) 4,4-Difluoro-5-methyl-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester 2-methyl ester

To a solution of 710 mg (2.76 mmol) of(2,5-cis)-5-methyl-4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 2-methyl ester in 10 mL of CH₂Cl₂ at −78° C. was added 800 μL(6.05 mmol) of N,N-diethylaminosulfur trifluoride (DAST). The reactionwas put under N₂, warmed to ambient temperature, and stirred for 18 h.The excess DAST was quenched by slowly adding the reaction mixture to 20mL of ice cooled saturated NaHCO_(3(aq.)). After vigorously stirring thebiphasic mixture for 10 min, the layers were separated. The aqueouslayer was extracted with CH₂Cl₂ (1×10 mL), then the combined organiclayers were back extracted with brine (1×10 mL), dried over MgSO₄,filtered, and concentrated to an oil. The product was purified viasilica gel chromatography, (75 mL silica gel) eluting with 10% ethylacetate/hexanes, then stepping to 20% ethyl acetate/hexanes aftercollection of the forerun to give the titled compound as a colorlessoil. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35 (dd, J=6.78, 3.05 Hz, 3H) 1.49(s, 9H) 2.37 (m, 1H) 2.65 (m, 1H) 3.76 (m, 3H) 4.09 (bs, 1H) 4.36 (bs,1H); MS (ESI) m/z=280 (M+H)⁺, 297 (M+NH₄)⁺, 302 (M+Na)⁺.

Example 95G (2,5-cis) 4,4-Difluoro-5-methyl-pyrrolidine-2-carboxylicacid methyl ester hydrochloride

To 363 mg (1.30 mmol) of 2,5cis-difluoro-5-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 2-methyl ester was added 3 mL of 4M HCl in dioxane. The solutionwas stirred at ambient temperature for 2 h, then concentrated in vacuoto furnish the titled compound as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.34 (dd, J=7.0, 1.5 Hz, 3H) 2.72 (m, 1H) 2.91 (m, 1H)3.78 (s, 3H) 3.93 (m, 1H) 4.76 (t, J=9.3 Hz, 1H) 10.49 (bs, 2H); MS(ESI) m/z=180 (M+H)⁺.

Example 95H1-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoyl)-(2,5-cis)-4,4-difluoro-5-methyl-pyrrolidine-2-carboxylicacid methyl ester

To 58 mg (0.23 mmol) of N-(tert-butoxycarbonyl)-S-leucine and 100 mg of(dimethylamino-((1,2,3)triazolo(4,5-b)pyridin-3-yloxy)-methylene)-dimethyl-ammoniumhexafluorophosphate (HATU) was added 1 mL of N-dimethylformamide, then90 μL (0.52 mmol) of N,N-diisopropylethylamine. The mixture was stirredfor 1 min, then added to another flask containing 50 mg (0.23 mmol) of(2,5-cis) 4,4-difluoro-5-methyl-pyrrolidine-2-carboxylic acid methylester hydrochloride. After 2 h, the reaction was diluted with 5 mL ofH₂O and extracted with diethyl ether (3×5 mL). The combined ether layerswere back extracted with 1M HCl_((aq.)), saturated NaHCO_(3(aq.)), andbrine (1×5 mL), dried over MgSO₄, filtered, and concentrated to an oil.The product was purified via silica gel chromatography, eluting with 30%ethyl acetate/hexanes to give the titled compound as a colorless foam.¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.88 (m, 6H) 1.31 (m, 3H) 1.36 (s, 9H)1.55 (m, 3H) 2.50 (m, 1H) 2.82 (m, 1H) 3.64 (m, 3H) 4.18 (m, 1H) 4.44(t, J=9.0 Hz, 1H) 4.71 (m, 1H) 7.32 (d, J=8.1 Hz, 1H); MS (ESI) m/z=393(M+H)⁺, 410 (M+NH₄)⁺, 415 (M+Na)⁺.

Example 95I1-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoyl)-(2,5-cis)-4,4-difluoro-5-methyl-pyrrolidine-2-carboxylicacid

To a solution of 69 mg (0.18 mmol) of1-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoyl)-(2,5-cis)-4,4-difluoro-5-methyl-pyrrolidine-2-carboxylicacid methyl ester in 2 mL of ethanol was added 0.4 mL (0.8 mmol) of 2MKOH_((aq.)). The reaction was stirred at ambient temperature for 1.5 h,then concentrated in vacuo. The residue was taken up in 5 mL of H₂O, andacidified with 2 mL of 1M HCl_((aq.)), then the suspension was extractedwith diethyl ether (3×5 mL). The combined ether layers were backextracted with brine (1×5 mL), dried over MgSO₄, filtered, andconcentrated to provide the titled compound as a colorless foam. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 0.88 (m, 6H) 1.31 (m, 3H) 1.37 (m, 9H) 1.57 (m,3H) 2.48 (m, 1H) 2.81 (m, 1H) 4.18 (m, 1H) 4.33 (t, J=9.2 Hz, 1H) 4.72(m, 1H) 7.30 (d, J=7.8 Hz, 1H), 12.80 (bs, 1H); MS (ESI) m/z=377 (M−H)⁺.

Example 95J(1-(S)((2,5-cis)-5-Carbamoyl-3,3-difluoro-2-methyl-pyrrolidine-1-carbonyl)-3-methyl-butyl)-carbamicacid tert-butyl ester

To a solution of 60 mg (0.159 mmol) of1-((S)-2-tert-butoxycarbonylamino-4-methyl-pentanoyl)-(2,5-cis)-4,4-difluoro-5-methyl-pyrrolidine-2-carboxylicacid in 1 mL of tetrahydrofuran was added 24 μL (0.22 mmol) ofN-methylmorpholine, then 24 μL (0.19 mmol) of isobutyl chloroformate.The mixture was stirred at ambient temperature for 1.5 h, then 0.3 mL of15M NH₄OH was added. After 3.5 h, the reaction was concentrated invacuo. The residue was taken up in 10 mL of ethyl acetate and extractedwith H₂O (1×3 mL), 1M HCl (1×3 mL), saturated NaHCO₃(aq.) (1×3 mL), andbrine (1×3 mL), dried over MgSO₄, filtered, and concentrated in vacuo tofurnish the titled compound as a colorless foam. TLC 75% ethylacetate/hexanes, stains with ninhydrin. ¹H NMR (300 MHz, DMSO-d₆) δ ppm0.88 (m, 6H) 1.30 (m, 3H) 1.36 (s, 9H) 1.55 (m, 3H) 2.31 (m, 1H) 2.64(m, 1H) 4.13 (m, 1H) 4.37 (t, J=9.0 Hz, 1H) 4.64 (m, 1H) 7.08 (s, 1H)7.27 (d, J=8.1 Hz, 1H) 7.38 (s, 1H); MS (ESI) m/z=378 (M+H)⁺, 395(M+NH₄)⁺, 400 (M+Na)⁺.

Example 95K(1-(S)-((2,5-cis)-5-Cyano-3,3-difluoro-2-methyl-pyrrolidine-1-carbonyl)-3-methyl-butyl)-carbamicacid tert-butyl ester

To 58 mg (0.15 mmol) of(1-(S)((2,5-cis)-5-carbamoyl-3,3-difluoro-2-methyl-pyrrolidine-1-carbonyl)-3-methyl-butyl)-carbamicacid tert-butyl ester was added 1 mL of pyridine, then 11 mg (0.16 mmol)of imidazole. After the imidazole had dissolved, the reaction was cooledwith an ice bath, and 30 mL (0.32 mmol) of phosphorous oxychloride wasadded. The reaction was stirred for 2 h, then concentrated in vacuo. Theresidue was taken up in 10 mL of ethyl acetate and extracted with 1MHCl_((aq.)) (2×5 mL), saturated NaHCO₃ (1×5 mL), and brine (1×5 mL),dried over MgSO₄, filtered, and concentrated to a foam. The product waspurified via silica gel chromatography, eluting with 20% ethylacetate/hexanes to give the titled compound as a colorless foam. ¹H NMR(300 MHz, DMSO-d₆) (mixture of rotamers, major rotamer only) δ ppm 0.90(m, 6H) 1.28 (m 1H) 1.40 (m, 12H) 1.61 (m, 2H) 2.99 (m, 2H) 4.16 (m, 1H)4.77 (m, 1H) 4.92 (m, 1H) 7.43 (d, J=7.8 Hz, 1H); MS (ESI) m/z=360(M+H)⁺, 377 (M+NH₄)⁺, 382 (M+Na)⁺.

Example 95(2S,5S)-4,4-difluoro-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile

To 34 mg (0.095 mmol) of(1-(S)-((2,5-cis)-5-cyano-3,3-difluoro-2-methyl-pyrrolidine-1-carbonyl)-3-methyl-butyl)-carbamicacid tert-butyl ester was added 0.5 mL of trifluoroacetic acid. Thesolution was allowed to stand at ambient temperature for 10 min, thenconcentrated in vacuo to give the titled compound as a colorless foam.¹H NMR (300 MHz, DMSO-d₆) (mixture of rotamers, major rotamer only) δppm 0.95 (m, 6H) 1.35 (m, 3H) 1.72 (m, 2H) 3.07 (m, 2H) 4.28 (m, 2H)4.76 (m, 1H) 5.03 (t, J=8.65 Hz, 1H) 8.31 (s, 3H); MS (ESI) m/z=260(M+H)⁺.

Example 96(2S,5R)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-vinylpyrrolidine-2-carbonitrileExample 96A(2S,5R)-1-((2S)-2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-5-trimethylsilanylethynyl-pyrrolidine-2-carboxylicacid methyl ester

To a stirred solution of methyl(5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (2 g, 8.87 mmol, Example1E) in dichloromethane (50 mL) at room temperature under nitrogen wasadded 4-dimethylaminopyridine (1.08 g, 8.87 mmol), 4-methylmorpholine(1.46 mL, 13.31 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl carbodiimidehydrochloride (2.04 g, 10.65 mmol), and Boc-Gly(cyclohexyl).OH. (2.7 g,10.65 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate andwashed with 1M HCl. The aqueous layer was further extracted with ethylacetate (2×). The combined ethyl acetate layers were dried (Na₂SO₄) andevaporated. Purification by flash chromatography 30% EtOAc/hexane gavethe desired compound as a white powder. MS (DCI) m/z 465 (M+H)⁺.

Example 96B(2S,5R)-1-((2S)-2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-5-ethynyl-pyrrolidine-2-carboxylicacid

To a stirred solution of 96A (4.3 g, 9.25 mmol), in MeOH (30 mL) and H₂O(30 mL) at room temperature was added LiOH—H₂O (0.58 g, 13.88 mmol). Thereaction mixture was stirred at ambient temperature overnight and thenevaporated. Water was added to the residue, and the mixture wasextracted with Et₂O (2×). The aqueous layer was acidified to pH ˜4 byadding 4% KHSO₄ dropwise. The clear solution was extracted with EtOAc(3×). Combined EtOAc layers were washed with brine, dried over (Na₂SO₄)and evaporated to give the desired compound as a white solid. MS (DCI)m/z 379 (M+H)⁺.

Example 96C((2S)-2-((2S,5R)-2-Carbamoyl-5-ethynyl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethyl)-carbamicacid tert-butyl ester

To a stirred solution of the compound from Example 96B (3.07 g, 8.11mmol) in THF (60 mL) at −15° C. under nitrogen was added4-methylmorpholine (1.07 mL, 9.73 mmol) and then isobutylchloroformate(1.2 mL, 8.92 mmol) over 2 minutes. A white precipitate was formed. Thereaction mixture was stirred at −15° C. under nitrogen for 30 minutes,and a solution of NH₃ in dioxane (81.10 mL, 40.55 mmol) was added. Thereaction mixture was quenched with 4% KHSO₄ to ˜pH 4 and extracted withEtOAc (3×). The organic extracts were combined, washed with brine, dried(Na₂SO₄) and evaporated. Purification by flash column chromatography (5%MeOH/CH₂Cl₂) gave the desired compound. MS (DCI) m/z 378 (M+H)⁺.

Example 96D((2S)-2-((2S,5R)-2-Cyano-5-ethynyl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethyl)-carbamicacid tert-butyl ester

To a stirred solution of Example 96E (1 g, 2.46 mmol) and imidazole(0.18 g, 2.64 mmol) in dry pyridine at −35° C. under N2 was added POCl₃dropwise. The reaction mixture was stirred between −35 and −20° C. for 2hours and then permitted to warm to room temperature. The reactionmixture was concentrated, CH₂Cl₂ was added, the white solids wereremoved by filtration, and the filterate was concentrated. The whitesolid was purified (30% EtOAc/hexane) to give the desired compound as afoam. MS (DCI) m/z 360 (M+H)⁺.

Example 96E((2S)-2-((2S,5R)-2-Cyano-5-vinyl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethyl)-carbamicacid tert-butyl ester

To a solution of((2S)-2-((2S,5R)-2-cyano-5-ethynyl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethyl)-carbamicacid tert-butyl ester (0.2 g, 0.53 mmol) and quinoline (0.22 ml) inEtOAc (20 ml) was stirred under hydrogen (20 psi) over 5% Pd/BaSO₄ (80mg). The mixture was stirred at room temperature for 7 minutes. Themixture was diluted with EtOAc and washed with 1.0M HCl. The organiclayer was dried over Na₂SO₄ and concentrated. Purification by flashchromatography (3% MeOH—CH₂Cl₂) gave the desired compound as an oil. MS(DCI) m/z 379 (M+H)⁺.

Example 96(2S,5R)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-vinylpyrrolidine-2-carbonitrile

The reaction mixture of((2S)-2-((2S,5R)-2-cyano-5-vinyl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethyl)-carbamicacid tert-butyl ester (0.03 mg, 0.087 mmol) and 4 M HCl in dioxane (0.15mL, 0.6 mmol) was stirred at room temperature for 2 h and evaporatedunder reduced pressure. The residue was triturated with ether to providethe titled compound as a white powder. MS (DCI) m/z 362 (M+H)⁺; ¹H NMR(300 MHz, MeOH) δ 1.4-1.9 (10H, m), 2.2-2.28 (2H, m), 2.4-2.68 (3H, m),3.19 (1H, d), 4.3 (1H, d), 4.8 (1H, t), 5.05 (1H, m), 5.9-6.04 (2H, m).

Example 98(2S,5S)-1-{N-((2R,5S)-hexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl}-5-methylpyrrolidine-2-carbonitrile

The title compound was prepared using the conditions described inExample 91 substituting 1-adamantanamine for cyclopentylamine. 1H NMR(300 MHz, Methanol-d4) δ ppm 1.36 (d, J=6.44 Hz, 3H) 1.67 (m, 4H) 1.98(m, 8H) 2.43 (m, 5H) 3.88 (m, 1H) 4.21 (m, 2H) 4.78 (t, J=7.80 Hz, 1H).MS (ESI) m/z 288 (M+H)⁺.

Example 99 (2S,5R)-5-ethynyl-1-(N-(1-tert-butoxycarbonyl-piperidin-4-yl)-glycyl)pyrrolidine-2-carbonitrile

Example 99 was prepared in the same way as Example 42 by substituting4-amino-piperidine-1-carboxylic acid tert-butyl ester fortrans-4-aminocyclohexanol. MS (ESI) m/z 361 (M+H)⁺.

Example 100(2S,5R)-5-ethynyl-1-(N-(1-(5-cyano-pyridin-2-yl)\piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile

Example 100 was prepared in the same manner as Example 31 bysubstituting 2-chloro-5-cyanopyridine for 5-bromonicotinitrile. MS (CI)m/z 363 (M+1)⁺.

Example 101(2S,5R)-1-{N-(1-(4-chlorobenzoyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same manner as Example 32 bysubstituting 4-chlorobenzoyl chloride for 4-chlorocarbonyl-benzoic acidmethyl ester. MS (CI) m/z 413 (M+1)⁺.

Example 102(2S,5R)-1-{N-(1-(3-cyanophenyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same manner as described inExamples 30 and 31 by substituting 3-bromobenzonitrile for5-bromonicotinonitrile and (4-methyl-piperidin-4-yl)carbamic acid benzylester for piperidin-4-yl-carbamic acid tert-butyl ester. MS (CI) m/z 376(M+1)⁺.

Example 103(2S,5R)-1-{N-(1-(4-cyanobenzoyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same manner as example 39 bysubstituting isonicotinyl chloride with 4-cyanobenzoyl chloride. MS (CI)m/z 404 (M+1)⁺.

Example 105(2S,5R)-1-{N-(1-(4-bromobenzoyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same manner as example 39 bysubstituting isonicotinyl chloride with 4-bromobenzoyl chloride. MS (CI)m/z 458 (M+1)⁺.

Example 106(2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same manner as example 29 bysubstituting 2-fluoropyridine with 2-chloro-4-(trifluoromethyl)pyridine.MS (CI) m/z 420 (M+1)⁺.

Example 107(2S,5R)-1-{N-(4-trans(4-cyano-2-fluorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 3,4-difluorobenzonitrile for 4-fluorobenzonitrile. MS (ESI)m/z 395 (M+H)⁺.

Example 108(2S,5R)-5-ethynyl-1-{N-(4-trans(3-fluorophenoxy)-1-methylcyclohexyl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 46 bysubstituting 1,3-difluorobenzene for 3-fluoropyridine. MS (ESI) m/z 384(M+H)⁺.

Example 109(2S,5R)-1-{N-(4-trans(3-cyanophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 3-fluorobenzonitrile for 4-fluorobenzonitrile. MS (ESI) m/z377 (M+H)⁺.

Example 111(2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 2,5-dichloropyridine for 4-fluorobenzonitrile. MS (ESI) m/z387 (M+H)⁺.

Example 112(2S,5R)-5-ethynyl-1-(N-(4-trans{(4′-fluoro-2-(trifluoromethyl)-1,1′-biphenyl-4-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 43 bysubstituting 1-bromo-4-fluoro-2-trifluoromethyl benzene for3-bromo-4-fluoro-1-trifluoromethyl benzene. MS (ESI) m/z 514 (M+H)⁺.

Example 113(2S,5R)-5-ethynyl-1-(N-(4-trans{(4′-fluoro-6-(trifluoromethyl)-1,1′-biphenyl-3-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 43 bysubstituting 2-bromo-4-fluoro-1-trifluoromethyl benzene for3-bromo-4-fluoro-1-trifluoromethyl benzene. MS (ESI) m/z 514 (M+H)⁺.

Example 114(2S,5R)-1-(N-{4-(3-cyano-4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 5-fluoro-2-trifluoromethyl-benzonitrile for4-fluorobenzonitrile. MS (ESI) m/z 445 (M+H)⁺.

Example 115(2S,5R)-1-{N-(4-trans(3-bromophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 1-bromo-3-fluoro-benzene for 4-fluorobenzonitrile. MS (ESI)m/z 431 (M+H)⁺.

Example 116(2S,5R)-1-{N-(4-trans(4-cyano-3-fluorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 2,4-difluorobenzonitrile for 4-fluorobenzonitrile. MS (ESI)m/z 395 (M+H)⁺.

Example 117(2S,5R)-1-(N-{4-(2-cyano-4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 2-fluoro-5-trifluoromethyl-benzonitrile for4-fluorobenzonitrile. MS (ESI) m/z 445 (M+H)⁺.

Example 118(2S,5R)-1-{N-(4-trans(3-cyanophenoxy)-1-methylcyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 46 bysubstituting 3-fluorobenzonitrile for 3-fluoropyridine. MS (ESI) m/z 391(M+H)⁺.

Example 119(2S,5R)-1-{N-(4-trans(4-chlorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 1-chloro-4-fluoro-benzene for 4-fluorobenzonitrile. MS(ESI) m/z 386 (M+H)⁺.

Example 120(2S,5R)-5-ethynyl-1-(N-(4-trans{(6-methyl-4-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 2-chloro-6-methyl-4-trifluoromethyl-pyridine for4-fluorobenzonitrile. MS (ESI) m/z 435 (M+H)⁺.

Example 121(2S,5R)-1-(N-{4-trans(2-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 2-fluoro-6-trifluoromethyl-benzonitrile for4-fluorobenzonitrile. MS (ESI) m/z 445 (M+H)⁺.

Example 122(2S,5R)-5-ethynyl-1-(N-{4-trans(4-pyridin-4-yl-3-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 43 bysubstituting 4-pyridyl boronic acid for 4-fluorophenyl boronic acid and2-bromo-5-fluorobenzotrifluoride for3-bromo-4-fluoro-1-trifluoromethylbenzene. MS (ESI) m/z 497 (M+H)⁺.

Example 123(2S,5R)-1-(N-{4-trans(3-cyano-5-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 3-fluoro-5-trifluoromethyl-benzonitrile for4-fluorobenzonitrile. MS (ESI) m/z 445 (M+H)⁺.

Example 124(2S,5R)-5-ethynyl-1-{N-(4-(4-fluorophenoxy)-1-methylcyclohexyl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 46 bysubstituting 1,4-difluorobenzene for 3-fluoropyridine. MS (ESI) m/z 384(M+H)⁺.

Example 125(2S,5R)-5-ethynyl-1-{N-(4-(3-fluorophenoxy)-1-methylcyclohexyl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 46 bysubstituting 1,3-difluorobenzene for 3-fluoropyridine. MS (ESI) m/z 384(M+H)⁺.

Example 127(2S,5R)-5-ethynyl-1-(N-{4-trans(3-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 1-fluoro-3-trifluoromethyl-benzene for4-fluorobenzonitrile. MS (ESI) m/z 420 (M+H)⁺.

Example 128(2S,5R)-1-(N-{4-trans((3-bromopyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 3-bromo-2-chloro-pyridine for 4-fluorobenzonitrile. MS(ESI) m/z 432 (M+H)⁺.

Example 129(2S,5R)-5-ethynyl-1-(N-(4-trans{(4-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 2-chloro-4-trifluoromethyl-pyridine for4-fluorobenzonitrile. MS (ESI) m/z 421 (M+H)⁺.

Example 130(2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)-1-methylcyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 46 bysubstituting 2,5-dichloropyridine for 3-fluoropyridine. MS (ESI) m/z 401(M+H)⁺.

Example 131(2S,5R)-1-{N-(4-trans(3-cyanophenoxy)-1-methylcyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 46 bysubstituting 3-fluorobenzonitrile for 3-fluoropyridine. MS (ESI) m/z 391(M+H)⁺.

Example 132(2S,5R)-5-ethynyl-1-(N-{4-trans(4-(trifluoromethyl)-5-(carboxy)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 2-fluoro-5-trifluoromethyl-benzoic acid for4-fluorobenzonitrile. MS (ESI) m/z 464 (M+H)⁺.

Example 133(2S,5R)-1-{N-(4-trans(3-chlorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 1-chloro-3-fluoro-benzene for 4-fluorobenzonitrile. MS(ESI) m/z 386 (M+H)⁺.

Example 134(2S,5R)-5-ethynyl-1-(N-(1-methyl-4-trans{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same manner as example 46 bysubstituting 2-chloro-5-trifluoromethylpyridine for 3-fluoropyridine.The titled compound is a mixture of diastereomers at the ether bearingcarbon. MS (CI) m/z 435 (M+1)⁺.

Example 135(2S,5R)-1-{N-(4-trans(4-bromophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 48 bysubstituting 1-bromo-4-fluorobenzene for 4-fluorobenzonitrile. MS (ESI)m/z 431 (M+H)⁺.

Example 136(2S,5R)-1-(N-{1,1-dimethyl-2-((3-cyano-6-methylpyridin-2-yl)amino)ethyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared using the same procedure as describedfor Example 155 by substituting 6-chloronicotinonitrile with2-chloro-3-cyano-6-methylpyridine. MS (DCI/NH₃) m/z 365 (M+H)⁺.

Example 137(2S,5R)-1-(N-(1,1-dimethyl-2-{(5-(trifluoromethyl)pyridin-2-yl)oxy}ethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared using the same procedure as describedfor Example 66 substituting 2-chloro-5-(trifluoromethyl)pyridine for6-chloronicotinonitrile. MS (DCI/NH₃) m/z 394 (M+H)⁺.

Example 138(2S,5R)-1-(N-{1,1-dimethyl-2-((3-cyano-6-methylpyridin-2-yl)oxy)ethyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared using the same procedure as describedfor Example 66 substituting 2-chloro-3-cyano-6-methylpyridine for6-chloronicotinonitrile. MS (DCI/NH₃) m/z 366 (M+H)⁺.

Example 139(2S,5R)-5-ethynyl-1-(N-(tetrahydrofuran-2-ylmethyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 42 bysubstituting C-(tetrahydro-furan-2-yl)-methylamine fortrans-4-aminocyclohexanol. MS (ESI) m/z 262 (M+H)⁺.

Example 140(2S,5R)-5-ethynyl-1-(N-(pyridin-2-ylmethyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same manner as example 42 bysubstituting C-pyridin-2-yl-methylamine for trans-4-aminocyclohexanol.MS (CI) m/z 435 (M+1)⁺.

Example 141(2S,5R)-5-ethynyl-1-(N-(2-pyridin-4-ylethyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same manner as example 42 bysubstituting 2-pyridin-4-yl-ethylamine for trans-4-aminocyclohexanol. MS(CI) m/z 283 (M+1)⁺.

Example 142(2S,5R)-5-ethynyl-1-{N-((1-tert-butoxycarbonylpiperidin-4-yl)methyl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 42 bysubstituting 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl esterfor trans-4-aminocyclohexanol. MS (ESI) m/z 375 (M+H)⁺.

Example 143(2S,5R)-5-ethynyl-1-{N-(3-(methylamino)propyl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared by treating Example 151 with 4 M HCl indioxane. MS (ESI) m/z 249 (M+H)⁺.

Example 144(2S,5R)-5-ethynyl-1-(N-(4-tert-butyloxycarbonylbutyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 42 bysubstituting 4-amino-butyric-acid tert-butyl ester fortrans-4-aminocyclohexanol. MS (ESI) m/z 320 (M+H)⁺.

Example 145(2S,5R)-5-ethynyl-1-(N-(3-hydroxy-2,2-dimethylpropyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared as described in Example 160substituting neopentanolamine for cyclopropylamine. MS (DCI/NH₃),m/z=264 (M+H)⁺.

Example 1462-{[2-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]amino}isonicotinonitrile

The titled compound was prepared using the same procedure as describedfor Example 155 by substituting 6-chloronicotinonitrile with2-chloro-4-cyanopyridine. MS (DCI/NH₃) m/z 351 (M+H)⁺.

Example 147(2S,5R)-1-(N-(1,1-dimethyl-2-{(4-(trifluoromethyl)pyrimidin-2-yl)amino}ethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared using the same procedure as describedfor Example 155 by substituting 6-chloronicotinonitrile with2-chloro-4-(trifluoromethyl)pyrimidine. MS (DCI/NH₃) m/z 395 (M+H)⁺.

Example 148 methyl6-{[2-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]amino}nicotinate

The titled compound was prepared using the same procedure as describedfor Example 155 substituting 6-chloronicotinonitrile with methyl6-chloronicotinate. MS (DCI/NH₃) m/z 424 (M+H)⁺.

Example 149(2S,5R)-1-{N-(2-(2-cyano-5-fluorophenoxy)-1,1-dimethylethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared using the same procedure as describedfor Example 66 by substituting 2,4-difluorobenzonitrile for6-chloronicotinonitrile. MS (DCI/NH₃) m/z 369 (M+H)⁺.

Example 150(2S,5R)-5-ethynyl-1-(N-(4-iodobenzyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 42 bysubstituting 4-iodo-benzylamine for trans-4-aminocyclohexanol. MS (ESI)m/z 394 (M+H)⁺.

Example 151 (2S,5R)-5-ethynyl-1-{N-(3-(methylamino)-3-tert butyloxycarbonylpropyl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 42 bysubstituting (3-amino-propyl)methyl carbamic acid tert-butyl ester fortrans-4-aminocyclohexanol. MS (ESI) m/z 349 (M+H)⁺.

Example 152(2S,5R)-5-ethynyl-1-(N-(4-carboxybutyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared by treating Example 144 with 4 M HCl indioxane. MS (ESI) m/z 263 (M+H)⁺.

Example 153(2S,5R)-1-(N-(2-{(3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino}ethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile

Example 153 was prepared in the same way as example 42 by substitutingN1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-ethane-1,2-diamine fortrans-4-aminocyclohexanol. MS (ESI) m/z 400 (M+H)+.

Example 154(2S,5R)-5-ethynyl-1-(N-(3-isopropoxypropyl)glycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 42 bysubstituting 3-isopropoxy propylamine for trans-4-aminocyclohexanol. MS(ESI) m/z 278 (M+H)⁺.

Example 155(2S,5R)-1-{N-(1,1-dimethyl-2-(5-cyanopyridin-2-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrileExample 155A 6-(2-Amino-2-methyl-propylamino)-nicotinonitrile

A mixture of 1,2-diamino-2-methylpropane (3.14 ml, 30 mmol), and6-chloronicotinonitrile (2.77 g, 20 mmol) were heated to 120° C. for 2days. The reaction mixture was filtered, and the inorganic salt wasrinsed with EtOAc. The filterate was concentrated under reduced pressureto provide the titled compound as a pale yellow solid. MS (DCI) m/z 191(M+H)⁺.

Example 155(2S,5R)-1-{N-(1,1-dimethyl-2-(5-cyanopyridin-2-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.05 g,0.255 mmol, Example 8D) in acetonitrile (3 mL) at room temperature undernitrogen was added 6-(2-amino-2-methyl-propylamino)-nicotinonitrile (0.1g, 0.51 mmol). The reaction mixture was stirred overnight and thenconcentrated under reduced pressure. The residue was flashchromatographed with 2% MeOH/CH₂Cl₂ to provide the desired compound as awhite solid. MS (DCI) m/z 351 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.03-2.5 (2H, m), 2.55 (2H, s), 2.1 (2H, s), 3.5 (1H, m), 3.82 (6H, s),3.9-4.6 (2H, m), 4.7-4.82 (1H, m), 4.88-5.5 (1H, m), 7.3-7.5 (3H, m).

Example 156(2S,5R)-1-(N-(2-(4-carboxyanilino)-1,1-dimethylethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrileExample 156A(2S,5R)-1-(N-(2-(4-tert-butoxycarbonyl)-anilino-1,1-dimethylethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared using the same procedure as describedfor Example 155 substituting tert-butyl 4-fluorobenzoate for6-chloronicotinonitrile. MS (DCI/NH₃) m/z 424 (M+H)⁺.

Example 156(2S,5R)-1-(N-(2-(4-carboxyanilino)-1,1-dimethylethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile

A mixture of the tert-butylbenzoate described above in 4 M HCl indioxane was stirred at 23° C. for 2 hours. The dioxane was removed invacuo, and the crude solid was triturated several times with diethylether. The resulting white solid was dried in vacuum oven overnight toafford the HCl salt of the titled compound. MS (DCI/NH₃) m/e 368 (M+H)⁺.

Example 157(2S,5R)-5-ethynyl-1-{N-(1-(1-hydroxy-1-methylethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 42 bysubstituting 2-(1-amino-cyclopentyl)-propan-2-ol fortrans-4-aminocyclohexanol. MS (ESI) m/z 304 (M+H)⁺.

Example 158(2S,5R)-5-ethynyl-1-{N-((2R,5S)-hexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 42 bysubstituting 3-noradamantanamine for trans-4-aminocyclohexanol. MS (ESI)m/z 334 (M+H)⁺.

Example 159 (2S,5R)-1-(N-cyclopentylglycyl-(N-methyl1-aminocyclopentanecarboxy)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 42 bysubstituting 1-amino-cyclopentane carboxylic acid methyl ester fortrans-4-aminocyclohexanol. MS (ESI) m/z 304 (M+H)⁺.

Example 160(2S,5R)-1-(N-cyclopropylglycyl)-5-ethynylpyrrolidine-2-carbonitrile

To a stirred solution of Example 8D (0.045 g, 0.228 mmol) inacetonitrile (2 mL) at room temperature under nitrogen was addedcyclopropylamine (0.032 ml, 0.457 mmol). The reaction mixture wasstirred overnight and then concentrated under reduced pressure. Theresidue was flash chromatographed with 3% MeOH/CH₂Cl₂ to provide thedesired compound as a pale yellow oil. MS m/z 218 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 1.5-2 (4H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m),3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05(1H, m).

Example 161(2S,5R)-5-ethynyl-1-(N-piperidin-4-ylglycyl)pyrrolidine-2-carbonitrile

The titled compound was prepared by treating Example 99 with 4 M HCl indioxane. MS (ESI) m/z 261 (M+H)⁺.

Example 162(2S,5R)-5-ethynyl-1-{N-((5R,7S)-3-hydroxy-1-adamantyl)glycyl}pyrrolidine-2-carbonitrile

To a stirred solution of Example 8D (0.06 g, 0.305 mmol) in acetonitrile(3 mL) at room temperature under nitrogen, was added3-amino-1-adamantanol (0.1 g, 0.61 mmol). The reaction mixture wasstirred for two days and then concentrated under reduced pressure. Theresidue was flash chromatographed with 5-7% MeOH/CH₂Cl₂ to provide thedesired compound as a pale yellow oil. MS (DCI) m/z 328 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 1.5-2 (14H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H,m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05(1H, m).

Example 163(2S,5R)-5-ethynyl-1-((3R)—N-tetrahydrofuran-3-ylglycyl)pyrrolidine-2-carbonitrile

To a stirred solution of Example 8D (0.03 g, 0.153 mmol) and potassiumcarbonate (0.2 g, 1.53 mmol) in acetonitrile (2 mL), at room temperatureunder nitrogen was added R(+)-3-aminotetrahydrofuran toluene-4-sulfonate(0.08 g, 0.32 mmol). The reaction mixture was stirred overnight and thenconcentrated under reduced pressure. The residue was flashchromatographed with 2% MeOH/CH₂Cl₂ to provide the desired compound as apale yellow oil. MS (DCI) m/z 248 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ1.5-2 (2H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d),3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m), 5.43-5.9(4H, m).

Example 164(2S,5R)-1-(N-cycloheptylglycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared as described in Example 160substituting cyclopropylamine with cycloheptylamine. MS (DCI) m/z 274(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.5-2 (12H, m), 2.11-2.21 (2H, m),2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t),5.01 (1H, m), 5.05 (1H, m).

Example 165(2S,5R)-1-(N-cyclobutylglycyl)-5-ethynylpyrrolidine-2-carbonitrile

The titled compound was prepared as described in Example 160substituting cyclopropylamine with cyclobutylamine. MS (DCI) m/z 232(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.5-2 (6H, m), 2.11-2.21 (2H, m),2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t),5.01 (1H, m), 5.05 (1H, m).

Example 166(2S,5R)-5-ethynyl-1-(3-methyl-L-valyl)pyrrolidine-2-carbonitrile

The titled compound was prepared according to the procedures for Example1F-J substituting N-(t-butoxycarbonyl)-L-t-butylglycine forN-(t-butoxycarbonyl)-L-leucine monohydrate in the step described inExample IF. MS (DCI/NH₃) m/z 233 (M+H)⁺.

Example 167(2S,5R)-5-ethynyl-1-(3-pyridin-4-yl-L-alanyl)pyrrolidine-2-carbonitrile

The titled compound was prepared in the same manner as example 1 bysubstituting (2S)-tert-butoxycarbonylamino-3-pyridin-4-yl-propionic acidfor N-(tert-butoxycabonyl)-L-leucine monohydrate. MS (CI) m/z 269(M+1)⁺.

Example 168 (2S,5R)-1-L-leucyl-5-prop-1-ynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 85 bysubstituting t-Boc-L-Leucine forBoc-cyclopentyl-L-glycine.dicyclohexylamine. MS (ESI) m/z 248 (M+H)⁺.

Example 169(2S,5R)-1-(3-methyl-L-valyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 85 bysubstituting Boc-L-tert-leucine forBoc-cyclopentyl-L-glycine.dicyclohexylamine. MS (ESI) m/z 248 (M+H)⁺.

Example 170(2S,5R)-1-(N-cyclobutylglycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 88 bysubstituting cyclobutylamine for cyclopentylamine. MS (ESI) m/z 246(M+H)⁺.

Example 171 (2S,5R)-1-(N-(4-transhydroxycyclohexyl)glycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 88 bysubstituting trans-4-aminocyclohexanol for cyclopentylamine. MS (ESI)m/z 290 (M+H)⁺.

Example 172(2S,5R)-1-{N-((2S)-2-hydroxycyclopentyl)glycyl}-5-prop-1-ynylpyrrolidine-2-carbonitrile

The titled compound was prepared in the same way as example 88 bysubstituting 2-amino-cyclopentanol for cyclopentylamine. MS (ESI) m/z276 (M+H)⁺.

Example 173(2S,5S)-5-methyl-1-{N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo(3.1.1)hept-3-yl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared using the methodology described inExample 91 substituting (+)-isopinocampheylamine for cyclopentylamine.MS (DCI) m/z 304 (M+H)⁺.

Example 174(2S,5S)-1-{N-((5R,7S)-3-hydroxy-1-adamantyl)glycyl}-5-methylpyrrolidine-2-carbonitrile

The titled compound was prepared using the methodology described inExample 91 substituting 3-amino-1-adamantanol for cyclopentylamine. MS(DCI) m/z 318 (M+H)⁺.

Example 175(2S,5S)-1-{N-(2-(3,4-dimethoxyphenyl)ethyl)glycyl}-5-methylpyrrolidine-2-carbonitrile

The titled compound was prepared using the methodology described inExample 91 substituting homoveratrylamine for cyclopentylamine. MS (DCI)m/z 332 (M+H)⁺.

Example 176(2S,5S)-4,4-difluoro-5-methyl-1-((5S)-5-methyl-L-prolyl)pyrrolidine-2-carbonitrile

The titled compound was prepared using methodologies described inExamples 6 and 95 substituting(2R,5S)-5-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl esterfor N-(tert-butoxycarbonyl)-S-leucine. MS (ESI) m/z=258 (M+H)⁺.

Example 177(2S,5S)-1-(N-isopropylglycyl)-5-methylpyrrolidine-2-carbonitrile

The titled compound was prepared using the methodology described inExample 91 substituting isopropylamine for cyclopentylamine. MS (DCI)m/z 210 (M+H)⁺.

Example 178 (2S,5S)-1-L-isoleucyl-5-methylpyrrolidine-2-carbonitrile

The titled compound was prepared using methodology described in Examples91, 28 and 6 substituting N-(tert-butoxycarbonyl)-L-isoleucine forN-(tert-butoxycarbonyl)-L-leucine hydrate. MS (DCI) m/z 224 (M+H)⁺.

Example 179(2S,5S)-5-methyl-1-{N-(2-(5-cyano-pyridin-2-ylamino)ethyl)glycyl}pyrrolidine-2-carbonitrile

The titled compound was prepared using methodologies described inExample 91 and in Villhauer, E. B.; Brinkman, J. A.; Naderi, G. B.;Burkey, B. F.; Dunning, B. E.; Prasad, K.; Mangold, B. L.; Russell, M.E.; Hughes, T. E. J. Med. Chem. 2003, 46, 2774-2789. MS (DCI) m/z 313(M+H)⁺.

Example 180(2S,5S)-5-methyl-1-((3S)-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)pyrrolidine-2-carbonitrile

The title compound was prepared as described in Example 28 substitutingBoc-L-Tic-OH for N-(tert-butoxycarbonyl)-L-leucine hydrate. MS (ESI) m/z270 (M+H)⁺.

Example 181(2S,5S)-1-(3-cyclopropyl-L-alanyl)-5-methylpyrrolidine-2-carbonitrile

The title compound was prepared as described in Example 28 substitutingbeta-cyclopropyl-L-alanine Boc for N-(tert-butoxycarbonyl)-L-leucinehydrate. MS (DCI) m/z 208 (M+H)⁺.

Example 182 (2S,5S)-5-methyl-1-D-prolylpyrrolidine-2-carbonitrile

The title compound was prepared as described in Example 28 substitutingBoc-L-proline for N-tert-butoxycarbonyl-L-leucine hydrate. MS (DCI) m/z322 (M+H)⁺.

Example 183(2S,5S)-1-(N-2,3-dihydro-1H-inden-1-ylglycyl)-5-methylpyrrolidine-2-carbonitrile

The titled compound was prepared using the methodology described inExample 91 substituting 1-aminoindane for cyclopentylamine. MS (DCI) m/z284 (M+H)⁺.

Example 184 (2S,5S)-5-methyl-1-L-valylpyrrolidine-2-carbonitrile

The title compound was prepared as described in Example 28 substitutingN-(tert-butoxycarbonyl)-L-valine for N-(tert-butoxycarbonyl)-L-leucinehydrate. MS (DCI) m/z 211 (M+H)⁺.

Example 185(2S,5S)-5-methyl-1-(4-methyl-L-leucyl)pyrrolidine-2-carbonitrile

The title compound was prepared as described in Example 28 substitutingN-(tert-butoxycarbonyl)-L-t-butyl-alanine forN-(tert-butoxycarbonyl)-L-leucine hydrate. MS (DCI) m/z 238 (M+H)⁺.

Example 186 (2S,5S)-1-(N-(4-transhydroxycyclohexyl)glycyl)-5-methylpyrrolidine-2-carbonitrile

The titled compound was prepared using the methodology described inExample 91 substituting trans-4-aminocyclohexanol for cyclopentylamine.MS (DCI) m/z 266 (M+H)⁺.

Example 187(2S,5S)-1-(N-(tert-butyl)glycyl)-5-methylpyrrolidine-2-carbonitrile

The titled compound was prepared using the methodology described inExample 91 substituting 7-butylamine for cyclopentylamine. MS (DCI) m/z224 (M+H)⁺.

Example 188(2S,5S)-5-methyl-1-((5S)-5-methyl-L-prolyl)pyrrolidine-2-carbonitrile

The title compound was prepared using the methodology described inExamples 28, 6, and 176. MS (DCI) m/z 222 (M+H)⁺.

Example 189(2S,5S)-1-(3-cyclohexyl-L-alanyl)-5-methylpyrrolidine-2-carbonitrile

The title compound was prepared as described in Example 28 substitutingN-(tert-butoxycarbonyl)-L-cyclohexylalanine forN-(tert-butoxycarbonyl)-L-leucine hydrate. MS (DCI) m/z 264 (M+H)⁺.

Example 1906-{[4-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-4-methylcyclohexyl]oxy}-N,N-dimethylnicotinamideExample 190A6-(4-amino-4-methyl-cyclohexyloxy)-N,N-dimethyl-nicotinamide

To a mixture of sodium hydride (240 mg, 6.0 mmol) in dimethylformamide(10 mL) at 0° C. was added Example 45F (258 mg, 2.0 mmol). The resultingmixture was stirred at 0° C. for 30 minutes, then Example 40A (473 mg,2.4 mmol) was added. It was heated to 60° C. for 2 hours and stirred for12 hours at room temperature. The reaction mixture was diluted withethyl acetate and washed with water (3 times) and brine. The organiclayer was dried (sodium sulfate), filtered, and concentrated underreduced pressure to provide the titled compound. MS (DCI) m/z 278(M+H)⁺.

Example 190

A mixture of Example 190A (194 mg, 0.31 mmol) and Example 8D (30 mg,0.153 mmol) in acetonitrile (1 mL) were stirred at 23° C. for 48 hours.The reaction mixture was stirred at room temperature for 48 hours,concentrated under reduced pressure and purified by HPLC to provide thetitled compound. MS (ESI) m/z 438 (M+H)⁺; ¹H NMR (300 MHz, MeOH-d₄) δppm 8.25 (d, 1H), 7.78 (dd, 1H), 6.86 (d, 1H), 4.95 (m, 1H), 4.86 (m,1H), 4.20 (AB quartet, 2H), 3.08 (s, 6H), 2.50-2.37 (m, 4H), 2.33 (m,1H), 2.16-1.98 (m, 4H) 1.93-1.73 (m, 4H), 1.49 (s, 3H).

Example 191(1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-N-(pyridin-2-ylmethyl)cyclopentanecarboxamideExample 191A (1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylicacid

To a cold solution (0° C.) of (1S,3R)-3-amino-cyclopentanecarboxylicacid (387 mg, 3 mmol) and NaOH (132 mg, 3.3 mmol) in tert-butanol (3.3mL) and water (3 ml) was added (Boc)₂O (655 mg, 3 mmol). The reactionmixture was stirred from 0° C. to room temperature for 1 hour. Themixture was washed with hexane (3 times), acidified with 1N HCl to pH=3,and extracted with ethyl acetate (3 times). The organic layer was dried(sodium sulfate), filtered, concentrated under reduced pressure andpurified by flash chromatography with 30% ethyl acetate/hexane toprovide the titled compound. MS (ESI) m/z 230 (M+H)⁺.

Example 191B(1S,3R)-{3-[(pyridin-2-ylmethyl)-carbamoyl]-cyclopentyl}-carbamic acidtert-butyl ester

To a solution of(1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (91.6 mg,0.4 mmol) in DMF (4 ml) was added pycoylamine (0.045 ml, 0.44 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC),(93 mg, 0.48 mmol), 1-hydroxybenzotriazole (HOBT), (82 mg, 0.6 mmol),and diisopropylethylamine (0.35 ml, 2 mmol). The mixture was stirred atroom temperature for 16 hours. The mixture was diluted with ethylacetate, washed with water (2 times) and brine. The organic layer wasdried (sodium sulfate), filtered, concentrated under reduced pressureand purified by flash chromatography with 3% methanol/dichloromethane toprovide the titled compound. MS (ESI) m/z 320 (M+H)⁺.

Example 191(1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-N-(pyridin-2-ylmethyl)cyclopentanecarboxamide

(1S,3R)-{3-[(pyridin-2-ylmethyl)-carbamoyl]-cyclopentyl}-carbamic acidtert-butyl ester (66 mg, 0.21 mmol) was dissolved in 4N HCl/dioxane (1ml) and the mixture was stirred at room temperature for 1 hour. Themixture was concentrated under reduced pressure. The residue was takenup in acetonitrile (1 ml), Example 8D (21 mg, 0.103 mmol) anddiisopropylethylamine (0.091 ml, 0.52 mmol) were added. The mixture wasstirred at room temperature for 48 hours, concentrated under reducedpressure and purified by HPLC to provide the titled compound. MS (ESI)m/z 380 (M+H)⁺; ¹H NMR (300 MHz, MeOH-d₄) δ ppm 8.63 (dd, 1H), 8.20 (m,1H), 7.66 (m, 2H), 4.62 (s, 2H), 4.20 (AB quartet, 2H), 3.81-3.68 (m,2H), 2.46-1.94 (m, 7H), 1.37 (m, 6H).

Example 192(1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-N-quinolin-2-ylcyclopentanecarboxamideExample 192A (1S,3R)-[3-(quinolin-2-ylcarbamoyl)-cyclopentyl]-carbamicacid tert-butyl ester

To a solution of Example 191A (91.6 mg, 0.4 mmol) in DMF (4 ml) wasadded 2-aminoquinoline (64 mg, 0.44 mmol), ED AC (93 mg, 0.48 mmol),HOBT (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 ml, 2 mmol). Themixture was stirred at room temperature overnight, diluted with ethylacetate, washed with water (2 times) and brine. The organic layer wasdried (sodium sulfate), filtered, concentrated under reduced pressureand purified by flash chromatography with 3% methanol/dichloromethane toprovide the titled compound. MS (ESI) m/z 356 (M+H)⁺.

Example 192(1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-N-quinolin-2-ylcyclopentanecarboxamide

A mixture of (1S,3R)-[3-(quinolin-2-ylcarbamoyl)-cyclopentyl]-carbamicacid tert-butyl ester (71 mg, 0.2 mmol) in 4N HCl/dioxane (1 ml) wasstirred at room temperature for 1 hour. The mixture was concentratedunder reduced pressure, taken up in acetonitrile (1 ml), Example 8D (20mg, 0.1 mmol) and diisopropylethylamine (0.087 ml, 0.5 mmol) were added.The mixture was stirred at room temperature for 48 hours, concentratedunder reduced pressure and purified by HPLC to provide the titledcompound. MS (ESI) m/z 416 (M+H)⁺; ¹H NMR (300 MHz, MeOH-d₄) δ ppm 8.63(dd, 1H), 8.20 (m, 1H), 7.66 (m, 2H), 4.29-4.20 (m, 2H), 3.80-3.70 (m,2H), 2.96 (m, 1H), 2.49-1.8 (m, 12H).

Example 193(2S,5R)-5-ethynyl-1-({[4-methyl-1-(5-nitropyridin-2-yl)piperidin-4-yl]-amino}acetyl)pyrrolidine-2-carbonitrileExample 193A

A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl esterhydrochloride salt (2.40 g, 8.45 mmol, Example 30B),2-chloro-5-nitropyridine (1.45 g, 9.15 mmol) and diisopropyl ethyl amine(5.2 mL) in dioxane (10 mL) in a sealed tube was heated to 82° C.overnight. The mixture was cooled, concentrated and then purified bychromatography (silica gel, eluting with 15% hexane/ethyl acetate to 30%ethyl acetate/hexane) to provide the titled compound (2.75 g) as ayellow solid. MS (CI) m/z 371 (M+1)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 9.03(d, 1H), 8.20 (dd, 1H), 7.37 (m, 5H), 6.57 (dd, 1H), 5.08 (s, 2H), 4.68(bs, 1H), 4.13-4.05 (m, 2H), 3.51-3.42 (m, 2H), 2.20-2.14 (m, 2H),1.72-1.62 (m, 2H), 1.43 (s, 3H).

Example 193B4-Methyl-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine

To a stirred solution of Example 193A (0.36 g, 0.97 mmol) inacetonitrile (7.0 mL) at room temperature was added iodotrimethysilane(0.25 mL, 1.5 mmol). The mixture was stirred at 50° C. for 30 minutesand then concentrated under reduced pressure. The solid residue waswashed with acetone and ether and filtered to provide titled compound(0.18 g). MS (CI) m/z 237 (M+1)⁺; ¹H NMR (300 MHz, CD₃OD) δ ppm 8.96 (d,1H), 8.21 (dd, 1H), 6.85 (d, 1H), 4.79 (m, 1H), 3.94-3.74 (m, 4H),1.69-1.55 (m, 4H), 1.21 (s, 3H).

Example 193(2S,5R)-5-ethynyl-1-({[4-methyl-1-(5-nitropyridin-2-yl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile

A mixture of Example 193B (180 mg, 0.77 mmol) and(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (156 mg,0.8 mmol, Example 8D) and diisopropylethylamine (0.2 mL) in acetonitrile(10 mL) was stirred at 23° C. for 72 hours. The mixture was concentratedunder reduced pressure, and the crude residue was purified bychromatography (silica gel, eluting with 96% dichloromethane/4%methanol/0.1% ammonium hydroxide) to provide the compound as a yellowfoam. The product was mixed with 4M HCl in dioxane (4 mL) and after 0.5hour, the solvents were removed under reduced pressure, and the residuewas solidified by trituration with diethyl ether filtered to provide thetitled compound as the HCl salt. MS (CI) m/z 397 (M+1)⁺; ¹H NMR (300MHz, methanol-d₄) δ ppm 8.96 (d, 1H), 8.20 (dd, 1H), 6.82 (d, 1H), 5.01(bs, 1H), 4.81-4.72 (m, 2H), 4.53-4.37 (m, 2H), 3.97-3.89 (m, 2H),3.80-3.72 (m, 3H), 3.62-3.56 (m, 1H), 3.09 (dd, 1H), 2.43-2.24 (m, 4H),1.75-1.61 (m, 2H), 1.21 (m, 3H).

Example 194(2S,5R)-5-ethynyl-1-[({4-methyl-1-[5-(methylsulfonyl)pyridin-2-yl]piperidin-4-yl}amino)acetyl]pyrrolidine-2-carbonitrileExample 194A 2-bromo-5-(methylsulfonyl)pyridine

To a solution of 2,5-dibromopyridine (5 g, 21.1 mmol) in THF (20 mL) at0° C. was slowly added 2M isopropylmagnesium chloride in THF (14.4 ml).The mixture was stirred at 0° C. for 1 hour, cooled to −15° C. followedby the dropwise addition of methane sulfonyl chloride in 5 mL THF. Themixture was slowly warmed up to room temperature, diluted with water (5mL) and t-butylmethyl ether (3×50 mL). The layers were separated and theaqueous layer extracted with t-butylmethyl ether (2×). The combinedorganic layers were washed with brine, dried MgSO₄, filtered andconcentrated under reduced pressure and purified by chromatography(silica gel, eluting with 30% hexane-70% ethyl acetate) to provide thetitled compound. MS (CI) m/z 237 (M+1)⁺, 254 (M+NH₄)⁺ ¹H NMR (300 MHz,CDCl₃) δ ppm: 8.92 (d, 1H), 8.06 (dd, 1H), 7.73 (d, 1H), 3.12 (s, 1H).

Example 194B5′-Methanesulfonyl-4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine

A solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl esterhydrochloride salt (0.37 g, 1.3 mmol, Example 30B),2-bromo-5-(methylsulfonyl)pyridine (0.27 g, 1.15 mmol) anddiisopropylethylamine (0.7 mL) in dioxane (4 mL) in a scaled tube washeated to 80° C. for 16 hours. The mixture was cooled, concentratedunder reduced pressure and purified by chromatography (silica gel,eluting with 5% hexane/ethyl acetate to 25% ethyl acetate/hexane) toprovide the titled compound (0.225 g) as a white solid. MS (CI) m/z 404(M+L)⁺; ¹H NMR (300 MHz, CDCl₃) δ ppm 8.63 (d, 1H), 7.86 (dd, 1H), 7.37(m, 5H), 6.65 (d, 1H), 5.07 (s, 2H), 4.67 (s, 1H), 4.04-3.96 (m, 2H),3.49-3.39 (m, 2H), 3.03 (s, 3H), 2.19-2.12 (m, 2H), 1.71-1.61 (m, 2H),1.41 (s, 3H).

Example 194C 4-(4-Amino-4-methyl-piperidine-1-carbonyl)-benzoic acidmethyl ester

A mixture of Example 194B (0.22 g, 0.55 mmol) and ammonium formate (0.14g, 2.2 mmol) in isopropanol (5.0 mL) was stirred at 80° C. for 30minutes, filtered through Celite and concentrated under reducedpressure. The solid residue was dried to provide titled compound (0.11g). MS (CI) m/z 270 (M+1)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.62 (d,1H), 7.83 (dd, 1H), 6.65 (d, 1H), 3.88-3.80 (m, 2H), 3.73-3.64 (m, 4H),3.03 (s, 3H), 1.79-1.58 (m, 4H), 1.35 (s, 3H).

Example 194(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-[5-(methanesulfonyl)pyridin-2-yl)piperidin-4-yl)amino)pyrrolidine-2-carbonitrile

A mixture of Example 194C (110 mg, 0.41 mmol) and(2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (90 mg,0.45 mmol. Example 8D) in acetonitrile (2 mL) with diisopropylethylamine(0.2 mL) was stirred at 23° C. for 72 hours. The mixture wasconcentrated under reduced pressure, and the crude residue was purifiedby chromatography (silica gel, eluting with 96% dichloromethane/4%methanol/0.1% ammonium hydroxide) to provide the compound as glassysolid. The product was mixed with 4M HCl in dioxane (4 mL) and after 0.5hour, the solvents were removed under reduced pressure, and the residuewas solidified by trituration with diethyl ether to provide the titledcompound as the HCl salt (61 mg). MS (CI) m/z 430 (M+1)⁺; ¹H NMR (300MHz, methanol-d₄) δ ppm: 8.52 (d, 1H), 8.15 (d, 1H), 7.29 (m, 1H), 4.91(m, 2H), 4.82 (m, 1H), 4.50-4.48 (m, 2H), 4.36-4.13 (q, 2H), 3.66 (s,3H), 3.47-3.37 (m, 2H), 3.23 (m, 1H), 2.50-2.31 (m, 4H), 2.12-2.02 (m,4H), 1.61 (s, 3H).

Example 195 methyl(1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)cyclopentanecarboxylateExample 195A (1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylicacid methyl ester

To a cold solution (0° C.) of Example 191A (458 mg, 2 mmol) in THF (2ml)/MeOH (2 ml) was added TMSCHN₂ (2 ml, 2N in hexane). The mixture wasstirred at room temperature for 2 hours, concentrated under reducedpressure and purified by flash chromatography with 30% acetone/hexane toprovide the titled compound. MS (ESI) m/z 244 (M+H)⁺.

Example 195 methyl(1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)cyclopentanecarboxylate

(1S,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid methylester (149 mg, 0.61 mmol) in 4N HCl/dioxane (1 ml) was stirred for 1hour and concentrated under reduced pressure. The residue was taken upin acetonitrile (1 ml) followed by the addition of Example 8D (60 mg,0.31 mmol) and diisopropylethylamine (0.27 ml, 1.53 mmol). The mixturewas stirred at room temperature for overnight, concentrated underreduced pressure and purified by HPLC to provide the titled compound. MS(ESI) m/z 304 (M+H)⁺; ¹H NMR (300 MHz, MeOH-d₄) δ ppm, 4.73 (m, 1H),4.66 (m, 1H), 3.68 (s, 3H), 3.69-3.52 (m, 2H), 2.79 (m, 1H), 2.40-1.54(m, 12H).

Example 196(2R,5S)-1-[(tert-butylamino)acetyl]pyrrolidine-2,5-dicarbonitrileExample 196A(2R,5S)-1-[2-(tert-Butoxycarbonyl-tert-butyl-amino)-acetyl]-pyrrolidine-2,5-dicarboxylicacid diethyl ester

Example 196A was prepared in the same way as Example 1F by substitutingdiethyl ester-(2R,5S)-2,5-pyrrolidinedicarboxylic acid (Gazetta ChimicaItaliana 1962, 92, 1093) for methyl(5R)-5-((trimethylsilyl)ethynyl)-L-prolinate andN-[(1,1-Dimethylethoxy)carbonyl]-N-(1,1-dimethylethyl)glycine methylester for N-(tert-butoxycabonyl)-L-leucine monohydrate. MS (CI) m/z429.2 (M+1)⁺; ¹³C NMR (100 MHz, CDCl₃) δ ppm 171.1, 170.6, 169.6, 79.7,61.6, 60.9, 59.9, 59.4, 55.62, 47.2, 29.8, 29.5, 28.4, 27.4, 14.0.

Example 196B(2R,5S)-1-[2-(tert-Butoxycarbonyl-tert-butyl-amino)-acetyl]-pyrrolidine-2,5-dicarboxylicacid dicarboxylic acid

Example 196B was prepared in the same way as Example 1G by substitutingExample 197A for methylN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-((trimethylsilyl)ethynyl)-L-prolinate.MS (CI) m/z 374.4 (M+1)⁺; ¹³C NMR (100 MHz, CDCl₃) δ ppm 175.5, 174.1,81.0, 60.7, 60.1, 56.0, 47.3, 30.5, 29.4, 28.4, 27.1.

Example 196C(2R,5S)-1-[2-(tert-Butoxycarbonyl-tert-butyl-amino)-acetyl]-pyrrolidine-2,5-dicarboxylicacid dicarboxamide

Example 196C was prepared in the same way as Example 1H by substitutingExample 197B forN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-proline. MS (ESI) m/z369.3 (M−1)⁺; ¹H NMR (100 MHz, CD₃OD) δ ppm 177.7, 177.5, 171.4, 81.3,63.0, 62.5, 57.0, 48.3, 32.6, 29.6, 28.8.

Example 196D(2R,5S)-1-[2-(tert-Butoxycarbonyl-tert-butyl-amino)-acetyl]-pyrrolidine-2,5-dicarboxylicacid dicarbonitrile

Example 196D was prepared in the same way as Example 1I by substitutingExample 197C forN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-prolinamide. MS (CI)m/z 335 (M+L)⁺; ¹³C NMR (100 MHz, CD₃OD) δ ppm 171.1, 156.8, 118.9,81.6, 57.2, 48.0, 32.3, 29.7, 29.6, 28.7.

Example 196(2R,5S)-1-[(tert-butylamino)acetyl]pyrrolidine-2,5-dicarbonitrile

Example 196 was prepared in the same way as Example 1 by substitutingExample 197D forN-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-pyrrolidine-2-carbonitrile.MS (CI) m/z 235 (M+1)⁺; ¹³C NMR (100 MHz, CD₃OD) δ ppm 165.8, 118.6,58.7, 48.3, 44.3, 32.1, 29.8, 25.8.

It will be evident to one skilled in the art that the present inventionis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

What is claimed is:
 1. A compound of formula (I),

or pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of CH₂, CHF and CF₂; R is selectedfrom the group consisting of alkylcarbonyl, arylcarbonyl, cyano,heterocyclecarbonyl, R₄R₅NC(O)—, B(OR₆)₂, (1,2,3)-dioxoborolane and4,4,5,5-tetramethyl-(1,2,3)-dioxoborolane; R₁ is selected from the groupconsisting of alkoxyalkyl, alkyl, alkylcarbonyl, alkenyl, alkynyl,allenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkyl,haloalkenyl, heterocyclealkyl, and hydroxyalkyl; R₂ and R₃ areindependently selected from the group consisting of hydrogen,alkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; or R₂ and R₃taken together with the atoms to which they are attached form a mono orbicyclic heterocycle selected from the group consisting of 2-indolinyl,2-indolyl, 3-isoquinoline, 2-piperazine, 2-piperidine, 2-pyrrolidine,2-pyrrole, 2-pyridine, 2-quinolinyl, 2-tetrahydroquinolinyl, and3-tetrahydroisoquinolinyl, wherein said heterocycle may be substitutedwith 0, 1, 2 or 3 substituents independently selected from the groupconsisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkoxy,arylalkyl, arylcarbonyl, aryloxy, carboxy, carboxyalkyl, cyano,cyanoalkyl, formyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, mercapto,nitro, phenyl, R_(A)R_(B)N—, R_(C)R_(D)NC(O)—, and R_(C)R_(D)NS(O)₂—;R₄, R₅ and R₆ are each independently selected from the group consistingof hydrogen, alkyl, and arylalkyl; R_(A) and R_(B) are eachindependently selected from the group consisting of alkyl,alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl; or R_(A) and R_(B)taken together with the nitrogen to which they are attached form a ringselected from the group consisting of piperidine, piperazine andmorpholine; and R_(C) and R_(D) are each independently selected from thegroup consisting of hydrogen and alkyl.
 2. The compound according toclaim 1, wherein R is cyano.
 3. The compound according to claim 1,wherein R is cyano; and R₁ is a member selected from the groupconsisting of alkyl, alkenyl, and alkynyl.
 4. The compound according toclaim 1, wherein R is cyano; R₁ is a member selected from the groupconsisting of alkyl, alkenyl, and alkynyl; and R₂ is a member selectedfrom the group consisting of alkoxyalkyl, alkyl, cycloalkyl,cycloalkylalkyl, arylalkyl, and heterocyclealkyl.
 5. The compoundaccording to claim 1, wherein R is cyano; R₁ is a member selected fromthe group consisting of alkyl, alkenyl, and alkynyl; R₂ is a memberselected from the group consisting of hydrogen, alkyl, cycloalkyl, andheterocycle; and R₃ is hydrogen.
 6. The compounds according to claim 5,that is a member selected from the group consisting of(2S,5R)-5-ethynyl-1-L-leucylpyrrolidine-2-carbonitrile;(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-vinylpyrrolidine-2-carbonitrile;(2S,5R)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5S)-5-ethyl-1-L-leucylpyrrolidine-2-carbonitrile;5S)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-ethylpyrrolidine-2-carbonitrile;(2S,5S)-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-L-leucylpyrrolidine-2-carbonitrile;(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-((2R)-2-amino-2-cyclohexylethanoyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5S)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-methylpyrrolidine-2-carbonitrile;(2S,5R)-1-((2S)-2-amino-2-cyclopentylethanoyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;(2S,5S)-4,4-difluoro-5-methyl-1-L-valylpyrrolidine-2-carbonitrile;(2S,5S)-4,4-difluoro-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile;(2S,5R)-1-((2S)-2-amino-2-cyclohexylethanoyl)-5-vinylpyrrolidine-2-carbonitrile;(2S,5R)-1-((2R)-2-amino-2-cyclopentylethanoyl)-5-vinylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(3-methyl-L-valyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(3-pyridin-4-yl-L-alanyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-L-leucyl-5-prop-1-ynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(3-methyl-L-valyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;(2S,5S)-1-L-isoleucyl-5-methylpyrrolidine-2-carbonitrile;(2S,5S)-1-(3-cyclopropyl-L-alanyl)-5-methylpyrrolidine-2-carbonitrile;(2S,5S)-5-methyl-1-L-valylpyrrolidine-2-carbonitrile;(2S,5S)-5-methyl-1-(4-methyl-L-leucyl)pyrrolidine-2-carbonitrile; and(2S,5S)-1-(3-cyclohexyl-L-alanyl)-5-methylpyrrolidine-2-carbonitrile. 7.The compound according to claim 1, wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₁ ishydrogen; and R₃ is cycloalkyl, wherein cycloalkyl is a member selectedfrom the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cycloheptyl, and cyclooctyl.
 8. The compound according to claim 7, thatis a member selected from the group consisting of(2S,5R)-1-{N-((1R,2R,4S)-bicyclo(2.2.1)hept-2-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-((1R,4S)-bicyclo(2.2.1)hept-2-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-1-adamantylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-cyclohexylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(1-(methoxymethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-((2S)-2-hydroxycyclopentyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-cyclopentylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(1-(hydroxymethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1-(hydroxymethyl)cyclopentyl)glycyl}-5-prop-1-ynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-cyclopentylglycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;(2S,5S)-1-(N-cyclopentylglycyl)-5-methylpyrrolidine-2-carbonitrile;(2S,5S)-1-{N-(1-(hydroxymethyl)cyclopentyl)glycyl}-5-methylpyrrolidine-2-carbonitrile;(2S,5S)-1-{N-((2R,5S)-hexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl}-5-methylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(1-(1-hydroxy-1-methylethyl)cyclopentyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-((2R,5S)-hexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-cyclopentylglycyl-(N-methyl1-aminocyclopentanecarboxy)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-cyclopropylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-((5R,7S)-3-hydroxy-1-adamantyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-cycloheptylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-cyclobutylglycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-cyclobutylglycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-((2S)-2-hydroxycyclopentyl)glycyl}-5-prop-1-ynylpyrrolidine-2-carbonitrile;(2S,5S)-5-methyl-1-{N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo(3.1.1)hept-3-yl)glycyl}pyrrolidine-2-carbonitrile;(2S,5S)-1-{N-((5R,7S)-3-hydroxy-1-adamantyl)glycyl}-5-methylpyrrolidine-2-carbonitrile;(1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-N-(pyridin-2-ylmethyl)cyclopentanecarboxamide;(1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-N-quinolin-2-ylcyclopentanecarboxamide;and methyl(1S,3R)-3-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)cyclopentanecarboxylate.9. The compound according to claim 1, wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ ishydrogen; R₃ is

R₇ is a member selected from the group consisting of hydrogen and alkyl;and R₉ is a member selected from the group consisting of hydrogen, aryl,and heterocycle.
 10. The compound according to claim 9, that is a memberselected from the group consisting of(2S,5R)-5-ethynyl-1-(N-(4-trans-hydroxycyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-trans-{(4′-fluoro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-trans(4-(trifluoromethoxy)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-hydroxy-1-methylcyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(pyridin-3-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-trans((5-chloropyridin-3-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(4-cyanophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-trans{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-trans(3-pyridin-4-yl-4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-trans(pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(5-cyano-pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-trans(pyrimidin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-trans(5-cyano-pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-trans(4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-((5-fluoropyridin-3-yl)oxy)-1-methylcyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-trans(4-carboxy-phenoxy)cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-trans(2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(4-cyano-2-methoxyphenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(1-methyl-4-trans(pyridin-2-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-trans((5-fluoropyridin-3-yl)oxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-trans((5-bromopyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-trans(pyridin-3-yloxy)cyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-prop-1-ynyl-1-(N-{4-(4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(4-cyano-2-fluorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-trans(3-fluorophenoxy)-1-methylcyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(3-cyanophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(1-methyl-4-{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-trans{(4′-fluoro-2-(trifluoromethyl)-1,1′-biphenyl-4-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-trans{(4′-fluoro-6-(trifluoromethyl)-1,1′-biphenyl-3-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-(3-cyano-4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(3-bromophenoxy)cyclohexybglycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(4-cyano-3-fluorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-(2-cyano-4-trans(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(3-cyanophenoxy)-1-methylcyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(4-chlorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-trans{(6-methyl-4-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-trans(2-cyano-3-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-trans(4-pyridin-4-yl-3-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-trans(3-cyano-5-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-(4-fluorophenoxy)-1-methylcyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-(3-fluorophenoxy)-1-methylcyclohexyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(1-methyl-4-{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-trans(3-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-trans((3-bromopyridin-2-yl)oxy)cyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-trans{(4-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{4-trans((5-chloropyridin-2-yl)oxy)-1-methylcyclohexyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(3-cyanophenoxy)-1-methylcyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-trans(2-carboxy-4-(trifluoromethyl)phenoxy)cyclohexyl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(3-chlorophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(1-methyl-4-trans{(5-(trifluoromethyl)pyridin-2-yl)oxy}cyclohexyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(4-trans(4-bromophenoxy)cyclohexyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-(4-transhydroxycyclohexyl)glycyl)-5-prop-1-ynylpyrrolidine-2-carbonitrile;(2S,5S)-1-(N-(4-transhydroxycyclohexyl)glycyl)-5-methylpyrrolidine-2-carbonitrile; and6-{[4-({2-[(2S,5R)-2-cyano-5-ethynylpyrrolidin-1-yl]-2-oxoethyl}amino)-4-methylcyclohexyl]oxy}-N,N-dimethylnicotinamide.11. The compound according to claim 1, wherein R is cyano; R₁ is amember selected from the group consisting of alkyl, alkenyl, andalkynyl; R₂ is hydrogen; R₃ is alkyl; wherein the alkyl group of R₃ isoptionally substituted with a member of the group consisting of alkoxy,alkoxycarbonyl, alkoxycarbonylNR_(a), alkylNR_(a), carboxy, and hydroxy;and R_(a) is a member selected from the group consisting of hydrogen andalkyl.
 12. The compound according to claim 11, that is selected from thegroup consisting of(2S,5R)-5-ethynyl-1-(N-(1,1,3,3-tetramethylbutyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-(tert-butyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-(1,1-dimethylpropyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(3-(methylamino)propyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-1-(N-(4-tert-butoxycarbonylbutyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(3-hydroxy-2,2-dimethylpropyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(3-(N-tert-butoxycarbonyl-N-methylamino)propyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-carboxybutyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(3-isopropoxypropyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5S)-1-(N-isopropylglycyl)-5-methylpyrrolidine-2-carbonitrile;(2S,5S)-1-(N-(tert-butyl)glycyl)-5-methylpyrrolidine-2-carbonitrile; and(2S,5S)-1-[(tert-butylamino)acetyl]pyrrolidine-2,5-dicarbonitrile. 13.The compound according to claim 1, wherein R is cyano; R₁ is a memberselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ ishydrogen; and R₃ is a member selected from the group consisting of aryland heterocycle; wherein said heterocycle is a member selected from thegroup consisting of azetidinyl, azepanyl, aziridinyl, diazepinyl,1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl,imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl,isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl,oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl,piperazinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl,thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl,thiazolidinyl, thienyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl,triazinyl, triazolyl, and trithianyl.
 14. The compound according toclaim 13, that is a member selected from the group consisting of(2S,5R)-5-ethynyl-1-(N-tetrahydro-2H-pyran-4-ylglycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-tetrahydrofuran-3-ylglycyl)pyrrolidine-2-carbonitrile;and(2S,5S)-1-(N-2,3-dihydro-1H-inden-1-ylglycyl)-5-methylpyrrolidine-2-carbonitrile.15. The compound according to claim 1, wherein R is cyano; R₁ is amember selected from the group consisting of alkyl, alkenyl, andalkynyl; R₂ is hydrogen; and R₃ is a member selected from the groupconsisting of arylalkyl and heterocyclealkyl.
 16. The compound accordingto claim 15, that is a member selected from the group of(2S,5R)-5-ethynyl-1-{N-(2-(4-fluorophenyl)-1,1-dimethylethyl)glycyl}pyrrolidine-2-carbonitrile;(2S,5S)-1-{N-(2-(3,4-dimethoxyphenyl)ethyl)glycyl}-5-methylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(tetrahydrofuran-2-ylmethyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(pyridin-2-ylmethyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(2-pyridin-4-ylethyl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N4(1-tert-butoxycarbonylpiperidin-4-yl)methyl)glycyl}pyrrolidine-2-carbonitrile;and(2S,5R)-5-ethynyl-1-(N-(4-iodobenzyl)glycyl)pyrrolidine-2-carbonitrile.17. The compound according to claim 1, wherein R is cyano; R₁ is amember selected from the group consisting of alkyl, alkenyl, andalkynyl; R₂ is hydrogen; R₃ is

R₇ is a member selected from the group consisting of hydrogen, alkyl andalkoxyalkyl; and R₈ is a member selected from the group consisting ofhydrogen, alkylcarbonyl, aryl and heterocycle.
 18. The compoundaccording to claim 17, that is a member selected from the groupconsisting of(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(3-cyano-pyridin-2-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(1-(3-cyano-pyridin-3-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1-(5-chloropyridin-2-yl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(1-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(5-carboxy-pyridin-2-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(4-methyl-1-(5-cyano-pyridin-3-yl)piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(1-tert-butoxycarbonyl-piperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(1-5-cyano-pyridin-2-ylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1-(3-cyanophenyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-{4-methyl-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl}glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-piperidin-4-ylglycyl)pyrrolidine-2-carbonitrile;and(2S,5R)-5-ethynyl-1-({[4-methyl-1-(5-nitropyridin-2-yl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile;and(2S,5R)-5-ethynyl-1-[({4-methyl-1-[5-(methylsulfonyl)pyridin-2-yl]piperidin-4-yl}amino)acetyl]pyrrolidine-2-carbonitrile.19. The compound according to claim 1, wherein R is cyano; R₁ isselected from the group consisting of alkyl, alkenyl, and alkynyl; R₂ ishydrogen; R₃ is

R₇ is a member selected from the group consisting of hydrogen, alkyl andalkoxyalkyl; and R₈ is a member selected from the group consisting ofarylcarbonyl and heterocyclecarbonyl.
 20. The compound according toclaim 19, that is a member selected from the group consisting of(2S,5R)-5-ethynyl-1-{N-(4-methyl-1-(4-methoxycarbonylbenzoyl)piperidin-4-yl)glycyl}pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1-(4-chlorobenzoyl)piperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-5-ethynyl-1-(N-(1-isonicotinoyl-4-methylpiperidin-4-yl)glycyl)pyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1-(4-chlorobenzoyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1-(4-cyanobenzoyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;and(2S,5R)-1-{N-(1-(4-bromobenzoyl)-4-methylpiperidin-4-yl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile.21. The compound according to claim 1, wherein R is cyano; R₁ is amember selected from the group consisting of alkyl, alkenyl, alkynyl,allenyl and cycloalkyl; R₂ is hydrogen; and R₃ is a member selected fromthe group consisting of aryl-O-alkyl-, aryl-NH-alkyl-,heterocycle-O-alkyl- and heterocycle-NH-alkyl-.
 22. The compoundaccording to claim 21, that is a member selected from the groupconsisting of(2S,5R)-1-{N-(1,1-dimethyl-2-(5-cyano-pyridin-2-yloxy)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1,1-dimethyl-2-(quinolin-4-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(2-(1,3-benzothiazol-2-ylamino)-1,1-dimethylethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{1,1-dimethyl-2-((3-cyano-6-methylpyridin-2-yl)amino)ethyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-(1,1-dimethyl-2-{(5-(trifluoromethyl)pyridin-2-yl)oxy}ethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-{1,1-dimethyl-2-((3-cyano-6-methylpyridin-2-yl)oxy)ethyl}glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1,1-dimethyl-2-(3-cyanopyridin-2-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-(1,1-dimethyl-2-{(4-(trifluoromethyl)pyrimidin-2-yl)amino}ethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1,1-dimethyl-2-(5-methoxycarbonylpyridin-2-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(2-(2-cyano-5-fluorophenoxy)-1,1-dimethylethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-(2-{(3-chloro-5-(trifluoromethyl)pyridin-2-yl)amino}ethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-{N-(1,1-dimethyl-2-(5-cyano-pyridin-2-ylamino)ethyl)glycyl}-5-ethynylpyrrolidine-2-carbonitrile;(2S,5R)-1-(N-(2-(4-carboxy-anilino)-1,1-dimethylethyl)glycyl)-5-ethynylpyrrolidine-2-carbonitrile;and(2S,5S)-5-methyl-1-{N-(2-(5-cyano-pyridin-2-ylamino)ethyl)glycyl}pyrrolidine-2-carbonitrile.23. The compound according to claim 1, wherein R is cyano; R₁ isselected from the group consisting of alkyl, alkenyl, and alkynyl; andR₂ and R₃ taken together with the atoms they are attached form a mono orbicyclic heterocycle selected from the group consisting of3-isoquinoline, 2-pyrrolidinyl, 2-quinolinyl, 2-tetrahydroquinolinyl,and 3-tetrahydroisoquinolinyl.
 24. The compound according to claim 23,that is a member selected from the group consisting of(2S,5R)-5-ethynyl-1-((3S)-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)pyrrolidine-2-carbonitrile;(2S,5S)-4,4-difluoro-5-methyl-1-((5S)-5-methyl-L-prolyl)pyrrolidine-2-carbonitrile;(2S,5S)-5-methyl-1-((3S)-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)pyrrolidine-2-carbonitrile;(2S,5S)-5-methyl-1-L-prolylpyrrolidine-2-carbonitrile; and(2S,5S)-5-methyl-1-((5S)-5-methyl-L-prolyl)pyrrolidine-2-carbonitrile.25. A method of treating diabetes, comprising administration of atherapeutically effective amount of a compound of formula (I),

(I), or pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of CH₂, CHF and CF₂; R is selectedfrom the group consisting of alkylcarbonyl, arylcarbonyl, cyano,heterocyclecarbonyl, R₄R₅NC(O)—, B(OR₆)₂, (1,2,3)-dioxoborolane and4,4,5,5-tetramethyl-(1,2,3)-dioxoborolane; R₁ is selected from the groupconsisting of alkoxyalkyl, alkyl, alkylcarbonyl, alkenyl, alkenyl,allenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkyl,haloalkenyl, heterocyclealkyl, and hydroxyalkyl; or R₂ and R₃ areindependently selected from the group consisting of hydrogen,alkoxyalkyl, alkyl, alkenyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; or R₂ and R₃taken together with the atoms to which they are attached form a mono orbicyclic heterocycle selected from the group consisting of 2-indolinyl,2-indolyl, 3-isoquinoline. 2-piperazine, 2-piperidine, 2-pyrrolidine,2-pyrrole, 2-pyridine, 2-quinolinyl, 2-tetrahydroquinolinyl, and3-tetrahydroisoquinolinyl, wherein said heterocycle may be substitutedwith 0, 1, 2 or 3 substituents independently selected from alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkenyl, aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkyl,hydroxy, hydroxyalkyl, mercapto, nitro, phenyl, R_(A)R_(B)N—,R_(C)R_(D)NC(O)—, and R_(C)R_(D)NS(O)₂—; R₄, R₅ and R₆ are eachindependently selected from the group consisting of hydrogen, alkyl, andarylalkyl; R_(A) and R_(B) are each independently selected from thegroup consisting of alkyl, alkylcarbonyl, alkoxycarbonyl, andalkylsulfonyl; or R_(A) and R_(B) taken together with the nitrogen towhich they are attached form a ring selected from the group consistingof piperidine, piperazine and morpholine; and R_(C) and R_(D) are eachindependently selected from the group consisting of hydrogen and alkyl.26. A method of treating type II diabetes, comprising administration ofa therapeutically effective amount of a compound of formula (I),

(I), or pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of CH₂, CHF and CF₂; R is selectedfrom the group consisting of alkylcarbonyl, arylcarbonyl, cyano,heterocyclecarbonyl, R₄R₅NC(O)—, B(OR₆)₂, (1,2,3)-dioxoborolane and4,4,5,5-tetramethyl-(1,2,3)-dioxoborolane; R₁ is selected from the groupconsisting of alkoxyalkyl, alkyl, alkylcarbonyl, alkenyl, alkenyl,allenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkyl,haloalkenyl, heterocyclealkyl, and hydroxyalkyl; R₂ and R₃ areindependently selected from the group consisting of hydrogen,alkoxyalkyl, alkyl, alkenyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; or R₂ and R₃taken together with the atoms to which they are attached form a mono orbicyclic heterocycle selected from the group consisting of 2-indolinyl,2-indolyl, 3-isoquinoline. 2-piperazine, 2-piperidine, 2-pyrrolidine,2-pyrrole, 2-pyridine, 2-quinolinyl, 2-tetrahydroquinolinyl, and3-tetrahydroisoquinolinyl, wherein said heterocycle may be substitutedwith 0, 1, 2 or 3 substituents independently selected from alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkenyl, aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkyl,hydroxy, hydroxyalkyl, mercapto, nitro, phenyl, R_(A)R_(B)N—,R_(C)R_(D)NC(O)—, and R_(C)R_(D)NS(O)₂—; R₄, R₅ and R₆ are eachindependently selected from the group consisting of hydrogen, alkyl, andarylalkyl; R_(A) and R_(B) are each independently selected from thegroup consisting of alkyl, alkylcarbonyl, alkoxycarbonyl, andalkylsulfonyl; or R_(A) and R_(B) taken together with the nitrogen towhich they are attached form a ring selected from the group consistingof piperidine, piperazine and morpholine; and R_(C) and R_(D) are eachindependently selected from the group consisting of hydrogen and alkyl.27. A method of treating hyperglycemia, comprising administration of atherapeutically effective amount of a compound of formula (I),

(I), or pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of CH₂, CHF and CF₂; R is selectedfrom the group consisting of alkylcarbonyl, arylcarbonyl, cyano,heterocyclecarbonyl, R₄R₅NC(O)—, B(OR₆)₂, (1,2,3)-dioxoborolane and4,4,5,5-tetramethyl-(1,2,3)-dioxoborolane; R₁ is selected from the groupconsisting of alkoxyalkyl, alkyl, alkylcarbonyl, alkenyl, alkenyl,allenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkyl,haloalkenyl, heterocyclealkyl, and hydroxyalkyl; R₂ and R₃ areindependently selected from the group consisting of hydrogen,alkoxyalkyl, alkyl, alkenyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; or R₂ and R₃taken together with the atoms to which they are attached form a mono orbicyclic heterocycle selected from the group consisting of 2-indolinyl,2-indolyl, 3-isoquinoline. 2-piperazine, 2-piperidine, 2-pyrrolidine,2-pyrrole, 2-pyridine, 2-quinolinyl, 2-tetrahydroquinolinyl, and3-tetrahydroisoquinolinyl, wherein said heterocycle may be substitutedwith 0, 1, 2 or 3 substituents independently selected from alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkenyl, aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkyl,hydroxy, hydroxyalkyl, mercapto, nitro, phenyl, R_(A)R_(B)N—,R_(C)R_(D)NC(O)—, and R_(C)R_(D)NS(O)₂—; R₄, R₅ and R₆ are eachindependently selected from the group consisting of hydrogen, alkyl, andarylalkyl; R_(A) and R_(B) are each independently selected from thegroup consisting of alkyl, alkylcarbonyl, alkoxycarbonyl, andalkylsulfonyl; or R_(A) and R_(B) taken together with the nitrogen towhich they are attached form a ring selected from the group consistingof piperidine, piperazine and morpholine; and R_(C) and R_(D) are eachindependently selected from the group consisting of hydrogen and alkyl.28. A method of treating Syndrome X, comprising administration of atherapeutically effective amount of a compound of formula I,

(I), or pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of CH₂, CHF and CF₂; R is selectedfrom the group consisting of alkylcarbonyl, arylcarbonyl, cyano,heterocyclecarbonyl, R₄R₅NC(O)—, B(OR₆)₂, (1,2,3)-dioxoborolane and4,4,5,5-tetramethyl-(1,2,3)-dioxoborolane; R₁ is selected from the groupconsisting of alkoxyalkyl, alkyl, alkylcarbonyl, alkenyl, alkenyl,allenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkyl,haloalkenyl, heterocyclealkyl, and hydroxyalkyl; R₂ and R₃ areindependently selected from the group consisting of hydrogen,alkoxyalkyl, alkyl, alkenyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl; or R₂ and R₃taken together with the atoms to which they are attached form a mono orbicyclic heterocycle selected from the group consisting of 2-indolinyl,2-indolyl, 3-isoquinoline, 2-piperazine, 2-piperidine, 2-pyrrolidine,2-pyrrole, 2-pyridine, 2-quinolinyl, 2-tetrahydroquinolinyl, and3-tetrahydroisoquinolinyl, wherein said heterocycle may be substitutedwith 0, 1, 2 or 3 substituents independently selected from alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkenyl, aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkyl,hydroxy, hydroxyalkyl, mercapto, nitro, phenyl, R_(A)R_(B)N—,R_(C)R_(D)NC(O)—, and R_(C)R_(D)NS(O)₂—; R₄, R₅ and R₆ are eachindependently selected from the group consisting of hydrogen, alkyl, andarylalkyl; R_(A) and R_(B) are each independently selected from thegroup consisting of alkyl, alkylcarbonyl, alkoxycarbonyl, andalkylsulfonyl; or R_(A) and R_(B) taken together with the nitrogen towhich they are attached form a ring selected from the group consistingof piperidine, piperazine and morpholine; and R_(C) and R_(D) are eachindependently selected from the group consisting of hydrogen and alkyl.29. A method of treating hyperinsulinemia, comprising administration ofa therapeutically effective amount of a compound of formula (I),

(I), or pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of CH₂, CHF and CF₂; R is selectedfrom the group consisting of alkylcarbonyl, arylcarbonyl, cyano,heterocyclecarbonyl, R₄R₅NC(O)—, B(OR₆)₂, (1,2,3)-dioxoborolane and4,4,5,5-tetramethyl-(1,2,3)-dioxoborolane; R₁ is selected from the groupconsisting of alkoxyalkyl, alkyl, alkylcarbonyl, alkenyl, alkenyl,allenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkyl,haloalkenyl, heterocyclealkyl, and hydroxyalkyl; R₂ and R₃ areindependently selected from the group consisting of hydrogen,alkoxyalkyl, alkyl, alkenyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl; or R₂ and R₃taken together with the atoms to which they are attached form a mono orbicyclic heterocycle selected from the group consisting of 2-indolinyl,2-indolyl, 3-isoquinoline. 2-piperazine, 2-piperidine, 2-pyrrolidine,2-pyrrole, 2-pyridine, 2-quinolinyl, 2-tetrahydroquinolinyl, and3-tetrahydroisoquinolinyl, wherein said heterocycle may be substitutedwith 0, 1, 2 or 3 substituents independently selected from alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkenyl, aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkyl,hydroxy, hydroxyalkyl, mercapto, nitro, phenyl, R_(A)R_(B)N—,R_(C)R_(D)NC(O)—, and R_(C)R_(D)NS(O)₂—; R₄, R₅ and R₆ are eachindependently selected from the group consisting of hydrogen, alkyl, andarylalkyl; R_(A) and R_(B) are each independently selected from thegroup consisting of alkyl, alkylcarbonyl, alkoxycarbonyl, andalkylsulfonyl; or R_(A) and R_(B) taken together with the nitrogen towhich they are attached form a ring selected from the group consistingof piperidine, piperazine and morpholine; and R_(C) and R_(D) are eachindependently selected from the group consisting of hydrogen and alkyl.30. A method of treating obesity, comprising administration of atherapeutically effective amount of a compound of formula (I),

(I), or pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of CH₂, CHF and CF₂; R is selectedfrom the group consisting of alkylcarbonyl, arylcarbonyl, cyano,heterocyclecarbonyl, R₄R₅NC(O)—, B(OR₆)₂, (1,2,3)-dioxoborolane and4,4,5,5-tetramethyl-(1,2,3)-dioxoborolane; R₁ is selected from the groupconsisting of alkoxyalkyl, alkyl, alkylcarbonyl, alkenyl, alkenyl,allenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkyl,haloalkenyl, heterocyclealkyl, and hydroxyalkyl; R₂ and R₃ areindependently selected from the group consisting of hydrogen,alkoxyalkyl, alkyl, alkenyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycle, heterocyclealkyl, and hydroxyalkyl; or R₂ and R₃taken together with the atoms to which they are attached form a mono orbicyclic heterocycle selected from the group consisting of 2-indolinyl,2-indolyl, 3-isoquinoline. 2-piperazine, 2-piperidine, 2-pyrrolidine,2-pyrrole, 2-pyridine, 2-quinolinyl, 2-tetrahydroquinolinyl, and3-tetrahydroisoquinolinyl, wherein said heterocycle may be substitutedwith 0, 1, 2 or 3 substituents independently selected from alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl,alkylthio, alkenyl, aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy,carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkyl,hydroxy, hydroxyalkyl, mercapto, nitro, phenyl, R_(A)R_(B)N—,R_(C)R_(D)NC(O)—, and R_(C)R_(D)NS(O)₂—; R₄, R₅ and R₆ are eachindependently selected from the group consisting of hydrogen, alkyl, andarylalkyl; R_(A) and R_(B) are each independently selected from thegroup consisting of alkyl, alkylcarbonyl, alkoxycarbonyl, andalkylsulfonyl; or R_(A) and R_(B) taken together with the nitrogen towhich they are attached form a ring selected from the group consistingof piperidine, piperazine and morpholine; and R_(C) and R_(D) are eachindependently selected from the group consisting of hydrogen and alkyl.